330
Views
1
CrossRef citations to date
0
Altmetric
Reviews

T cell transgressions: Tales of T cell form and function in diverse disease states

, , &
Pages 475-516 | Received 10 Feb 2021, Accepted 20 Apr 2021, Published online: 21 Jun 2021

References

  • Gameiro J, Nagib P, Verinaud L. The thymus microenvironment in regulating thymocyte differentiation. Cell Adh Migr. 2010;4(3):382–390. doi:10.4161/cam.4.3.11789.
  • Carmona LM, Fugmann SD, Schatz DG. Collaboration of RAG2 with RAG1-like proteins during the evolution of V(D)J recombination. Genes Dev. 2016;30(8):909–917. doi:10.1101/gad.278432.116.
  • Klein L, Kyewski B, Allen PM, Hogquist KA. Positive and negative selection of the T cell repertoire: what thymocytes see (and don’t see). Nat Rev Immunol. 2014;14(6):377–391. doi:10.1038/nri3667.
  • Kono M, Maeda K, Stocton-Gavanescu I, et al. Pyruvate kinase M2 is requisite for Th1 and Th17 differentiation. JCI Insight. 2019;4(12). doi:10.1172/jci.insight.127395.
  • Kondo K, Ohigashi I, Takahama Y. Thymus machinery for T-cell selection. Int Immunol. 2019;31(3):119–125. doi:10.1093/intimm/dxy081.
  • Ueno T, Saito F, Gray DHD, et al. CCR7 signals are essential for cortex-medulla migration of developing thymocytes. J Exp Med. 2004;200(4):493–505. doi:10.1084/jem.20040643.
  • Esensten JH, Helou YA, Chopra G, Weiss A, Bluestone JA. CD28 Costimulation: from mechanism to therapy. Immunity. 2016;44(5):973–988. doi:10.1016/j.immuni.2016.04.020.
  • Courtney AH, Lo W-L, Weiss A. TCR signaling: mechanisms of initiation and propagation. Trends Biochem Sci. 2018;43(2):108–123. doi:10.1016/j.tibs.2017.11.008.
  • Hatada MH, Lu X, Laird ER, et al. Molecular basis for interaction of the protein tyrosine kinase ZAP-70 with the T-cell receptor. Nature. 1995;377(6544):32–38. doi:10.1038/377032a0.
  • Deindl S, Kadlecek TA, Brdicka T, et al. Structural basis for the inhibition of tyrosine kinase activity of ZAP-70. Cell. 2007;129(4):735–746. doi:10.1016/j.cell.2007.03.039.
  • Yan Q, Barros T, Visperas PR, et al. Structural basis for activation of ZAP-70 by phosphorylation of the SH2-kinase linker. Mol Cell Biol. 2013;33(11):2188–2201. doi:10.1128/MCB.01637-12.
  • Thill PA, Weiss A, Chakraborty AK. Phosphorylation of a tyrosine residue on Zap70 by Lck and its subsequent binding via an SH2 domain may be a key gatekeeper of T cell receptor signaling in vivo. Mol Cell Biol. 2016;36(18):2396–2402. doi:10.1128/MCB.00165-16.
  • Balagopalan L, Coussens NP, Sherman E, Samelson LE, Sommers CL. The LAT story: a tale of cooperativity, coordination, and choreography. Cold Spring Harb Perspect Biol. 2010;2(8):a005512. doi:10.1101/cshperspect.a005512.
  • Liu SK, Fang N, Koretzky GA, McGlade CJ. The hematopoietic-specific adaptor protein gads functions in T-cell signaling via interactions with the SLP-76 and LAT adaptors. Curr Biol. 1999;9(2):67–75. doi:10.1016/S0960-9822(99)80017-7.
  • Zhang W, Trible RP, Zhu M, et al. Association of Grb2, Gads, and phospholipase C-gamma 1 with phosphorylated LAT tyrosine residues. Effect of LAT tyrosine mutations on T cell angigen receptor-mediated signaling. J Biol Chem. 2000;275(30):23355–23361. doi:10.1074/jbc.M000404200.]
  • Castro CD, Boughter CT, Broughton AE, Ramesh A, Adams EJ. Diversity in recognition and function of human γδ T cells. Immunol Rev. 2020;298(1):134–152. doi:10.1111/imr.12930.
  • Huang W, Na L, Fidel PL, Schwarzenberger P. Requirement of interleukin-17A for systemic anti-Candida albicans host defense in mice. J Infect Dis. 2004;190(3):624–631. doi:10.1086/422329.
  • Weaver CT, Harrington LE, Mangan PR, Gavrieli M, Murphy KM. Th17: an effector CD4 T cell lineage with regulatory T cell ties. Immunity. 2006;24(6):677–688. doi:10.1016/j.immuni.2006.06.002.
  • Dominguez-Villar M, Hafler DA. Regulatory T cells in autoimmune diseases. Nat Immunol. 2018;19(7):665–673. doi:10.1038/s41590-018-0120-4.
  • Al K, Gerlach S. C. T cell fate mapping and lineage tracing technologies probing clonal aspects underlying the generation of CD8 T cell subsets. Scand. J. Immunol. 2020;92:e12983.
  • Raphael I, Joern RR, Forsthuber TG. Memory CD4+ T cells in immunity and autoimmune diseases. Cells. 2020;9(3):531. doi:10.3390/cells9030531.
  • Taniuchi I. CD4 helper and CD8 cytotoxic T cell differentiation. Annu Rev Immunol. 2018;36:579–601. doi:10.1146/annurev-immunol-042617-053411.
  • Hsieh C, Macatonia S, Tripp C, et al. Development of TH1 CD4+ T cells through IL-12 produced by Listeria-induced macrophages. Science. 1993;260(5107):547–549. doi:10.1126/science.8097338.
  • Amsen D, Spilianakis CG, Flavell RA. How are T(H)1 and T(H)2 effector cells made?Curr Opin Immunol. 2009;21(2):153–160. doi:10.1016/j.coi.2009.03.010.
  • Djuretic IM, Levanon D, Negreanu V, et al. Transcription factors T-bet and Runx3 cooperate to activate Ifng and silence Il4 in T helper type 1 cells. Nat Immunol. 2007;8(2):145–153. doi:10.1038/ni1424.
  • Usui T, Preiss JC, Kanno Y, et al. T-bet regulates Th1 responses through essential effects on GATA-3 function rather than on IFNG gene acetylation and transcription. J Exp Med. 2006;203(3):755–766. doi:10.1084/jem.20052165.
  • Luckheeram RV, Zhou R, Verma AD, Xia B. CD4+T cells: differentiation and functions. Clin Dev Immunol. 2012;2012:1–12. doi:10.1155/2012/925135.
  • Zhu J, Paul WE. CD4 T cells: fates, functions, and faults. Blood. 2008;112(5):1557–1569. doi:10.1182/blood-2008-05-078154.
  • Pennock ND, White JT, Cross EW, et al. T cell responses: naive to memory and everything in between. Adv Physiol Educ. 2013;37(4):273–283. doi:10.1152/advan.00066.2013.
  • Chiang EY, Kolumam GA, Yu X, et al. Targeted depletion of lymphotoxin-alpha-expressing TH1 and TH17 cells inhibits autoimmune disease. Nat Med. 2009;15(7):766–773. doi:10.1038/nm.1984.
  • Kim HP, Imbert J, Leonard WJ. Both integrated and differential regulation of components of the IL-2/IL-2 receptor system. Cytokine Growth Factor Rev. 2006;17(5):349–366. doi:10.1016/j.cytogfr.2006.07.003.
  • Williams MA, Tyznik AJ, Bevan MJ. Interleukin-2 signals during priming are required for secondary expansion of CD8+ memory T cells. Nature. 2006;441(7095):890–893. doi:10.1038/nature04790.
  • Engel M, Sidwell T, Vasanthakumar A, Grigoriadis G, Banerjee A. Thymic regulatory T cell development: role of signalling pathways and transcription factors. Clin Dev Immunol. 2013;2013:1–8. doi:10.1155/2013/617595.
  • Owen DL, Sjaastad LE, Farrar MA. Regulatory T cell development in the thymus. J Immunol. 2019;203(8):2031–2041. doi:10.4049/jimmunol.1900662.
  • Wuest TY, Willette-Brown J, Durum SK, Hurwitz AA. The influence of IL-2 family cytokines on activation and function of naturally occurring regulatory T cells. J Leukoc Biol. 2008;84(4):973–980. doi:10.1189/jlb.1107778.
  • Zhu J. T helper cell differentiation, heterogeneity, and plasticity. Cold Spring Harb. Perspect. Biol. 2018;10
  • Zhu J, Paul WE. Peripheral CD4+ T-cell differentiation regulated by networks of cytokines and transcription factors. Immunol Rev. 2010;238(1):247–262. doi:10.1111/j.1600-065X.2010.00951.x.
  • van Hamburg JP, de Bruijn MJW, de Almeida CR, et al. Enforced expression of GATA3 allows differentiation of IL-17-producing cells, but constrains Th17-mediated pathology. Eur J Immunol. 2008;38(9):2573–2586. doi:10.1002/eji.200737840.
  • Sokol CL, Chu N-Q, Yu S, et al. Basophils function as antigen-presenting cells for an allergen-induced T helper type 2 response. Nat Immunol. 2009;10(7):713–720. doi:10.1038/ni.1738.
  • Taylor-Robinson AW, Phillips RS. Functional characterization of protective CD4+ T-cell clones reactive to the murine malaria parasite Plasmodium chabaudi. Immunology. 1992;77(1):99–105.
  • Kopf M, Le Gros G, Bachmann M, et al. Disruption of the murine IL-4 gene blocks Th2 cytokine responses. Nature. 1993;362(6417):245–248. doi:10.1038/362245a0.
  • Steinke JW, Borish L. Th2 cytokines and asthma. Interleukin-4: its role in the pathogenesis of asthma, and targeting it for asthma treatment with interleukin-4 receptor antagonists. Respir Res. 2001;2(2):66–70. [Database] doi:10.1186/rr40.
  • Doucet C, Brouty-Boyé D, Pottin-Clemenceau C, Jasmin C, Canonica GW, Azzarone B. IL-4 and IL-13 specifically increase adhesion molecule and inflammatory cytokine expression in human lung fibroblasts. Int Immunol. 1998;10(10):1421–1433. doi:10.1093/intimm/10.10.1421.
  • Le Gros G, Ben-Sasson SZ, Seder R, Finkelman FD, Paul WE. Generation of interleukin 4 (IL-4)-producing cells in vivo and in vitro: IL-2 and IL-4 are required for in vitro generation of IL-4-producing cells. J Exp Med. 1990;172(3):921–929. doi:10.1084/jem.172.3.921.
  • Swain SL, Weinberg AD, English M, Huston G. IL-4 directs the development of Th2-like helper effectors. J Immunol Baltim Md 1950. 1990;145:3796–3806.
  • Coffman R, Seymour B, Hudak S, Jackson J, Rennick D. Antibody to interleukin-5 inhibits helminth-induced eosinophilia in mice. Science. 1989;245(4915):308–310. doi:10.1126/science.2787531.
  • Martinez-Moczygemba M, Huston DP. Biology of common beta receptor-signaling cytokines: IL-3, IL-5, and GM-CSF. J Allergy Clin Immunol. 2003;112(653–665):666. quiz
  • Yamaguchi Y, Suda T, Ohta S, Tominaga K, Miura Y, Kasahara T. Analysis of the survival of mature human eosinophils: interleukin-5 prevents apoptosis in mature human eosinophils. Blood. 1991;78(10):2542–2547. doi:10.1182/blood.V78.10.2542.2542.
  • Longphre M, Li D, Gallup M, et al. Allergen-induced IL-9 directly stimulates mucin transcription in respiratory epithelial cells. J Clin Invest. 1999;104(10):1375–1382.,. doi:10.1172/JCI6097.
  • Couper KN, Blount DG, Riley EM. IL-10: the master regulator of immunity to infection. J Immunol. 2008;180(9):5771–5777. doi:10.4049/jimmunol.180.9.5771.
  • Wynn TA. IL-13 effector functions. Annu Rev Immunol. 2003;21(1):425–456. doi:10.1146/annurev.immunol.21.120601.141142.
  • Fallon PG, Ballantyne SJ, Mangan NE, et al. Identification of an interleukin (IL)-25-dependent cell population that provides IL-4, IL-5, and IL-13 at the onset of helminth expulsion. J Exp Med. 2006;203(4):1105–1116. doi:10.1084/jem.20051615.
  • Kleinschek MA, Owyang AM, Joyce-Shaikh B, et al. IL-25 regulates Th17 function in autoimmune inflammation. J Exp Med. 2007;204(1):161–170. doi:10.1084/jem.20061738.
  • Zaiss DM, Yang L, Shah PR, et al. Amphiregulin, a TH2 cytokine enhancing resistance to nematodes. Science. 2006;314(5806):1746. doi:10.1126/science.1133715.
  • Zhang S. The role of transforming growth factor β in T helper 17 differentiation. Immunology. 2018;155(1):24–35. doi:10.1111/imm.12938.
  • Durant L, Watford WT, Ramos HL, et al. Diverse targets of the transcription factor STAT3 contribute to T cell pathogenicity and homeostasis. Immunity. 2010;32(5):605–615. doi:10.1016/j.immuni.2010.05.003.
  • Yang XO, Pappu BP, Nurieva R, et al. T helper 17 lineage differentiation is programmed by orphan nuclear receptors ROR alpha and ROR gamma. Immunity. 2008;28(1):29–39. doi:10.1016/j.immuni.2007.11.016.
  • Zhang S, Takaku M, Zou L, et al. Reversing SKI-SMAD4-mediated suppression is essential for TH17 cell differentiation. Nature. 2017;551(7678):105–109. doi:10.1038/nature24283.
  • Zhang J, Zhang Y, Wang Q, et al. Interleukin-35 in immune-related diseases: protection or destruction. Immunology. 2019;157(1):13–20. doi:10.1111/imm.13044.
  • Annunziato F, Cosmi L, Santarlasci V, et al. Phenotypic and functional features of human Th17 cells. J Exp Med. 2007;204(8):1849–1861. doi:10.1084/jem.20070663.
  • Ivanov II, McKenzie BS, Zhou L, et al. The orphan nuclear receptor RORgammat directs the differentiation program of proinflammatory IL-17+ T helper cells. Cell. 2006;126(6):1121–1133. doi:10.1016/j.cell.2006.07.035.
  • Gaffen SL. Structure and signalling in the IL-17 receptor family. Nat Rev Immunol. 2009;9(8):556–567. doi:10.1038/nri2586.
  • Hymowitz SG, Filvaroff EH, Yin JP, et al. IL-17s adopt a cystine knot fold: structure and activity of a novel cytokine, IL-17F, and implications for receptor binding. Embo J. 2001;20(19):5332–5341. doi:10.1093/emboj/20.19.5332.
  • Yao Z, Fanslow WC, Seldin MF, et al. Herpesvirus saimiri encodes a new cytokine, IL-17, which binds to a novel cytokine receptor. Immunity. 1995;3(6):811–821. doi:10.1016/1074-7613(95)90070-5.
  • Korn T, Reddy J, Gao W, et al. Myelin-specific regulatory T cells accumulate in the CNS but fail to control autoimmune inflammation. Nat Med. 2007;13(4):423–431. doi:10.1038/nm1564.
  • Nurieva R, Yang XO, Martinez G, et al. Essential autocrine regulation by IL-21 in the generation of inflammatory T cells. Nature. 2007;448(7152):480–483. doi:10.1038/nature05969.
  • Leonard WJ, Spolski R. Interleukin-21: a modulator of lymphoid proliferation, apoptosis and differentiation. Nat Rev Immunol. 2005;5(9):688–698. doi:10.1038/nri1688.
  • Bettelli E, Carrier Y, Gao W, et al. Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature. 2006;441(7090):235–238. doi:10.1038/nature04753.
  • McGeachy MJ, Bak-Jensen KS, Chen Y, et al. TGF-beta and IL-6 drive the production of IL-17 and IL-10 by T cells and restrain T(H)-17 cell-mediated pathology. Nat Immunol. 2007;8(12):1390–1397. doi:10.1038/ni1539.
  • Wang C, Yosef N, Gaublomme J, et al. CD5L/AIM regulates lipid biosynthesis and restrains Th17 cell pathogenicity. Cell. 2015;163(6):1413–1427. doi:10.1016/j.cell.2015.10.068.
  • Chang K-K, Liu L-B, Jin L-P, et al. IL-27 triggers IL-10 production in Th17 cells via a c-Maf/RORγt/Blimp-1 signal to promote the progression of endometriosis. Cell Death Dis. 2017;8(3):e2666–e2666. doi:10.1038/cddis.2017.95.
  • Xu J, Yang Y, Qiu G, et al. c-Maf regulates IL-10 expression during Th17 polarization. J Immunol. 2009;182(10):6226–6236. doi:10.4049/jimmunol.0900123.
  • Ghoreschi K, Laurence A, Yang X-P, et al. Generation of pathogenic TH17 cells in the absence of TGF-β signalling. Nature. 2010;467(7318):967–971. doi:10.1038/nature09447.
  • Langrish CL, Chen Y, Blumenschein WM, et al. IL-23 drives a pathogenic T cell population that induces autoimmune inflammation. J Exp Med. 2005;201(2):233–240. doi:10.1084/jem.20041257.
  • Lee Y, Awasthi A, Yosef N, et al. Induction and molecular signature of pathogenic TH17 cells. Nat Immunol. 2012;13(10):991–999. doi:10.1038/ni.2416.
  • Chung Y, Chang SH, Martinez GJ, et al. Critical regulation of early Th17 Cell differentiation by interleukin-1 signaling. Immunity. 2009;30(4):576–587. doi:10.1016/j.Immuni.2009.02.007.
  • Wu B, Zhang S, Guo Z, et al. The TGF-β superfamily cytokine Activin-A is induced during autoimmune neuroinflammation and drives pathogenic Th17 cell differentiation. Immunity. 2021;54(2):308–323.e6. doi:10.1016/j.immuni.2020.12.010.
  • Ahern PP, Schiering C, Buonocore S, et al. Interleukin-23 drives intestinal inflammation through direct activity on T cells. Immunity. 2010;33(2):279–288. doi:10.1016/j.immuni.2010.08.010.
  • Meyer Zu Horste G, Wu C, Wang C, et al. RBPJ controls development of pathogenic Th17 cells by regulating IL-23 receptor expression. Cell Rep. 2016;16(2):392–404. doi:10.1016/j.celrep.2016.05.088.
  • Codarri L, Gyülvészi G, Tosevski V, et al. RORγt drives production of the cytokine GM-CSF in helper T cells, which is essential for the effector phase of autoimmune neuroinflammation. Nat Immunol. 2011;12(6):560–567. doi:10.1038/ni.2027.
  • Jain R, Chen Y, Kanno Y, et al. Interleukin-23-induced transcription factor Blimp-1 promotes pathogenicity of T helper 17 cells. Immunity. 2016;44(1):131–142. doi:10.1016/j.immuni.2015.11.009.
  • Sonderegger I, Iezzi G, Maier R, et al. GM-CSF mediates autoimmunity by enhancing IL-6-dependent Th17 cell development and survival. J Exp Med. 2008;205(10):2281–2294. doi:10.1084/jem.20071119.
  • Liang SC, Tan X-Y, Luxenberg DP, et al. Interleukin (IL)-22 and IL-17 are coexpressed by Th17 cells and cooperatively enhance expression of antimicrobial peptides. J Exp Med. 2006;203(10):2271–2279. doi:10.1084/jem.20061308.
  • Zheng Y, Danilenko DM, Valdez P, et al. Interleukin-22, a T(H)17 cytokine, mediates IL-23-induced dermal inflammation and acanthosis. Nature. 2007;445(7128):648–651. doi:10.1038/nature05505.
  • Sakaguchi S. Naturally arising CD4+ regulatory t cells for immunologic self-tolerance and negative control of immune responses. Annu Rev Immunol. 2004;22:531–562. doi:10.1146/annurev.immunol.21.120601.141122.
  • Martinez GJ, Zhang Z, Chung Y, et al. Smad3 differentially regulates the induction of regulatory and inflammatory T cell differentiation. J Biol Chem. 2009;284(51):35283–35286. doi:10.1074/jbc.C109.078238.
  • Yang CY, Best JA, Knell J, et al. The transcriptional regulators Id2 and Id3 control the formation of distinct memory CD8+ T cell subsets. Nat Immunol. 2011;12(12):1221–1229. doi:10.1038/ni.2158.
  • Zheng SG, Wang J, Horwitz DA. Cutting edge: Foxp3 + CD4 + CD25+ regulatory T cells induced by IL-2 and TGF-beta are resistant to Th17 conversion by IL-6. J Immunol. 2008;180(11):7112–7116. 1950 doi:10.4049/jimmunol.180.11.7112.
  • Wing JB, Tay C, Sakaguchi S. Control of regulatory T cells by Co-signal molecules. Adv Exp Med Biol. 2019;1189:179–210. doi:10.1007/978-981-32-9717-3_7.
  • Owen DL, Mahmud SA, Sjaastad LE, et al. Thymic regulatory T cells arise via two distinct developmental programs. Nat Immunol. 2019;20(2):195–205. doi:10.1038/s41590-018-0289-6.
  • Santamaria JC, Borelli A, Irla M. Regulatory T cell heterogeneity in the thymus: impact on their functional activities. Front Immunol. 2021;12:643153.
  • Peligero-Cruz C, Givony T, Sebé-Pedrós A, et al. IL18 signaling promotes homing of mature Tregs into the thymus. eLife. 2020;9. doi:10.7554/eLife.58213.
  • Nikolouli E, Elfaki Y, Herppich S, et al. Recirculating IL-1R2+ Tregs fine-tune intrathymic Treg development under inflammatory conditions. Cell Mol Immunol. 2021;18(1):182–193. doi:10.1038/s41423-019-0352-8.
  • Brunkow ME, Jeffery EW, Hjerrild KA, et al. Disruption of a new forkhead/winged-helix protein, scurfin, results in the fatal lymphoproliferative disorder of the scurfy mouse. Nat Genet. 2001;27(1):68–73. doi:10.1038/83784.
  • Kuniyasu Y, Takahashi T, Itoh M, et al. Naturally anergic and suppressive CD25(+)CD4(+) T cells as a functionally and phenotypically distinct immunoregulatory T cell subpopulation. Int Immunol. 2000;12(8):1145–1155. doi:10.1093/intimm/12.8.1145.
  • Chen WJun, Jin W, Hardegen N, et al. Conversion of peripheral CD4 + CD25− Naive T cells to CD4 + CD25+ regulatory T cells by TGF-β induction of transcription factor Foxp3. J Exp Med. 2003;198(12):1875–1886. doi:10.1084/jem.20030152.
  • Li Y, Chu N, Hu A, et al. Increased IL-23p19 expression in multiple sclerosis lesions and its induction in microglia. Brain. 2007;130(Pt 2):490–501. doi:10.1093/brain/awl273.
  • Jutel M, Akdis CA. T-cell regulatory mechanisms in specific immunotherapy. In Blaser, K, ed. Chemical Immunology and Allergy. KARGER, 2008;94:158–177.
  • Ouyang W, Rutz S, Crellin NK, Valdez PA, Hymowitz SG. Regulation and functions of the IL-10 family of cytokines in inflammation and disease. Annu Rev Immunol. 2011;29(1):71–109. doi:10.1146/annurev-immunol-031210-101312.
  • Asseman C, Mauze S, Leach MW, Coffman RL, Powrie F. An essential role for interleukin 10 in the function of regulatory T cells that inhibit intestinal inflammation. J Exp Med. 1999;190(7):995–1004. doi:10.1084/jem.190.7.995.
  • Collison LW, Pillai MR, Chaturvedi V, Vignali DAA. Regulatory T cell suppression is potentiated by target T cells in a cell contact, IL-35- and IL-10-dependent manner. J Immunol. 2009;182(10):6121–6128. doi:10.4049/jimmunol.0803646.
  • Kavazović I, Polić B, Wensveen FM. Cheating the hunger games; mechanisms controlling clonal diversity of CD8 effector and memory populations. Front Immunol. 2018;9:2831. doi:10.3389/fimmu.2018.02831.
  • Mescher MF, Curtsinger JM, Agarwal P, et al. Signals required for programming effector and memory development by CD8+ T cells. Immunol Rev. 2006;211(1):81–92. doi:10.1111/j.0105-2896.2006.00382.x.
  • St Paul M, Ohashi PS. The roles of CD8+ T cell subsets in antitumor immunity. Trends Cell Biol. 2020;30(9):695–704. doi:10.1016/j.tcb.2020.06.003.
  • Chang JT, Wherry EJ, Goldrath AW. Molecular regulation of effector and memory T cell differentiation. Nat Immunol. 2014;15(12):1104–1115. doi:10.1038/ni.3031.
  • Daniels MA, Teixeiro E. TCR signaling in T cell memory. Front Immunol. 2015;6 doi:10.3389/fimmu.2015.00617.
  • Knudson KM, Goplen NP, Cunningham CA, Daniels MA, Teixeiro E. Low-affinity T cells are programmed to maintain normal primary responses but are impaired in their recall to low-affinity ligands. Cell Rep. 2013;4(3):554–565. doi:10.1016/j.celrep.2013.07.008.
  • Chen Y, Zander R, Khatun A, Schauder DM, Cui W. Transcriptional and epigenetic regulation of effector and memory CD8 T cell differentiation. Front Immunol. 2018;9:2826. doi:10.3389/fimmu.2018.02826.
  • Thaventhiran JED, Fearon DT, Gattinoni L. Transcriptional regulation of effector and memory CD8+ T cell fates. Curr Opin Immunol. 2013;25(3):321–328. doi:10.1016/j.coi.2013.05.010.
  • Ji Y, Pos Z, Rao M, et al. Repression of the DNA-binding inhibitor Id3 by Blimp-1 limits the formation of memory CD8+ T cells. Nat Immunol. 2011;12(12):1230–1237. doi:10.1038/ni.2153.
  • Samji T, Khanna KM. Understanding memory CD8+ T cells. Immunol Lett. 2017;185:32–39. doi:10.1016/j.imlet.2017.02.012.
  • Valbon SF, Condotta SA, Richer MJ. Regulation of effector and memory CD8(+) T cell function by inflammatory cytokines. Cytokine. 2016;82:16–23. doi:10.1016/j.cyto.2015.11.013.
  • Zhang N, Bevan MJ. CD8(+) T cells: foot soldiers of the immune system. Immunity. 2011;35(2):161–168. doi:10.1016/j.immuni.2011.07.010.
  • Andersen MH, Schrama D, Thor Straten P, Becker JC. Cytotoxic T cells. J Invest Dermatol. 2006;126(1):32–41. doi:10.1038/sj.jid.5700001.
  • Szabo SJ, Sullivan BM, Stemmann C, et al. Distinct effects of T-bet in TH1 lineage commitment and IFN-gamma production in CD4 and CD8 T cells. Science. 2002;295(5553):338–342. doi:10.1126/science.1065543.
  • Tummers B, Green DR. Caspase-8: regulating life and death. Immunol Rev. 2017;277(1):76–89. doi:10.1111/imr.12541.
  • Schroder K, Hertzog PJ, Ravasi T, Hume DA. Interferon-gamma: an overview of signals, mechanisms and functions. J Leukoc Biol. 2004;75(2):163–189. doi:10.1189/jlb.0603252.
  • Nagata S. Fas-mediated apoptosis. Adv Exp Med Biol. 1996;406:119–124. doi:10.1007/978-1-4899-0274-0_12.
  • Voskoboinik I, Whisstock JC, Trapani JA. Perforin and granzymes: function, dysfunction and human pathology. Nat Rev Immunol. 2015;15(6):388–400. doi:10.1038/nri3839.
  • Su MW-C, Pyarajan S, Chang J-H, et al. Fratricide of CD8+ cytotoxic T lymphocytes is dependent on cellular activation and perforin-mediated killing. Eur J Immunol. 2004;34(9):2459–2470. doi:10.1002/eji.200425096.
  • Joshi NS, Cui W, Chandele A, et al. Inflammation directs memory precursor and short-lived effector CD8(+) T cell fates via the graded expression of T-bet transcription factor. Immunity. 2007;27(2):281–295. doi:10.1016/j.immuni.2007.07.010.
  • Doherty PC, Hou S, Tripp RA. CD8+ T-cell memory to viruses. Curr Opin Immunol. 1994;6(4):545–552. doi:10.1016/0952-7915(94)90139-2.
  • Hammarlund E, Lewis MW, Hansen SG, et al. Duration of antiviral immunity after smallpox vaccination. Nat Med. 2003;9(9):1131–1137. doi:10.1038/nm917.
  • Nolz JC. Molecular mechanisms of CD8(+) T cell trafficking and localization. Cell Mol Life Sci. 2015;72(13):2461–2473. doi:10.1007/s00018-015-1835-0.
  • Gebhardt T, Mackay LK. Local immunity by tissue-resident CD8+ memory T cells. Front. Immunol. 2012;3
  • Cua DJ, Tato CM. Innate IL-17-producing cells: the sentinels of the immune system. Nat Rev Immunol. 2010;10(7):479–489. doi:10.1038/nri2800.
  • He D, Wu L, Kim HK, et al. CD8+ IL-17-producing T cells are important in effector functions for the elicitation of contact hypersensitivity responses. J Immunol. 2006;177(10):6852–6858. doi:10.4049/jimmunol.177.10.6852.
  • Villanova F, Flutter B, Tosi I, et al. Characterization of innate lymphoid cells in human skin and blood demonstrates increase of NKp44+ ILC3 in psoriasis. J Invest Dermatol. 2014;134(4):984–991. doi:10.1038/jid.2013.477.
  • Ramirez-Carrozzi V, Sambandam A, Luis E, et al. IL-17C regulates the innate immune function of epithelial cells in an autocrine manner. Nat Immunol. 2011;12(12):1159–1166. doi:10.1038/ni.2156.
  • Iwakura Y, Ishigame H, Saijo S, Nakae S. Functional Specialization of Interleukin-17 Family Members. Immunity. 2011;34(2):149–162. doi:10.1016/j.immuni.2011.02.012.
  • Li H, Chen J, Huang A, et al. Cloning and characterization of IL-17B and IL-17C, two new members of the IL-17 cytokine family. Proc Natl Acad Sci USA. 2000;97(2):773–778. doi:10.1073/pnas.97.2.773.
  • Starnes T, Broxmeyer HE, Robertson MJ, Hromas R. Cutting edge: IL-17D, a novel member of the IL-17 family, stimulates cytokine production and inhibits hemopoiesis. J. Immunol. Baltim. Md 1950. 2002;169:642–646.
  • Muñoz-Ruiz M, Sumaria N, Pennington DJ, Silva-Santos B. Thymic determinants of γδ T cell differentiation. Trends Immunol. 2017;38(5):336–344. doi:10.1016/j.it.2017.01.007.
  • Liang SC, Long AJ, Bennett F, et al. An IL-17F/A heterodimer protein is produced by mouse Th17 cells and induces airway neutrophil recruitment. J Immunol. 2007;179(11):7791–7799. doi:10.4049/jimmunol.179.11.7791.
  • Wright JF, Bennett F, Li B, et al. The human IL-17F/IL-17A heterodimeric cytokine signals through the IL-17RA/IL-17RC receptor complex. J Immunol. 2008;181(4):2799–2805. 1950 doi:10.4049/jimmunol.181.4.2799.
  • Rickel EA, Siegel LA, Yoon B-RP, et al. Identification of functional roles for both IL-17RB and IL-17RA in mediating IL-25-induced activities. J Immunol. 2008;181(6):4299–4310. doi:10.4049/jimmunol.181.6.4299.
  • Shi Y, Ullrich SJ, Zhang J, et al. A novel cytokine receptor-ligand pair. Identification, molecular characterization, and in vivo immunomodulatory activity. J Biol Chem. 2000;275(25):19167–19176. doi:10.1074/jbc.M910228199.
  • Novatchkova M, Leibbrandt A, Werzowa J, Neubüser A, Eisenhaber F. The STIR-domain superfamily in signal transduction, development and immunity. Trends Biochem Sci. 2003;28(5):226–229. doi:10.1016/S0968-0004(03)00067-7.
  • Qian Y, Liu C, Hartupee J, et al. The adaptor Act1 is required for interleukin 17-dependent signaling associated with autoimmune and inflammatory disease. Nat Immunol. 2007;8(3):247–256. doi:10.1038/ni1439.
  • Schwandner R, Yamaguchi K, Cao Z. Requirement of tumor necrosis factor receptor-associated factor (TRAF)6 in interleukin 17 signal transduction. J Exp Med. 2000;191(7):1233–1240. doi:10.1084/jem.191.7.1233.
  • Liu C, Qian W, Qian Y, et al. Act1, a U-box E3 ubiquitin ligase for IL-17 signaling. Sci Signal. 2009;2(92):ra63–ra63. doi:10.1126/scisignal.2000382.
  • Napetschnig J, Wu H. Molecular basis of NF-κB signaling. Annu Rev Biophys. 2013;42(1):443–468. doi:10.1146/annurev-biophys-083012-130338.
  • Hata K, Andoh A, Shimada M, et al. IL-17 stimulates inflammatory responses via NF-κB and MAP kinase pathways in human colonic myofibroblasts. Am J Physiol Gastrointest Liver Physiol. 2002;282(6):G1035–G1044. doi:10.1152/ajpgi.00494.2001.
  • Ruddy MJ, Wong GC, Liu XK, et al. Functional cooperation between interleukin-17 and tumor necrosis factor-alpha is mediated by CCAAT/enhancer-binding protein family members. J Biol Chem. 2004;279(4):2559–2567. doi:10.1074/jbc.M308809200.
  • Bulek K, Liu C, Swaidani S, et al. The inducible kinase IKKi is required for IL-17-dependent signaling associated with neutrophilia and pulmonary inflammation. Nat Immunol. 2011;12(9):844–852. doi:10.1038/ni.2080.
  • Qu F, Gao H, Zhu S, et al. TRAF6-dependent Act1 phosphorylation by the IκB kinase-related kinases suppresses interleukin-17-induced NF-κB activation. Mol Cell Biol. 2012;32(19):3925–3937. doi:10.1128/MCB.00268-12.
  • Herjan T, Yao P, Qian W, et al. HuR is required for IL-17-induced Act1-mediated CXCL1 and CXCL5 mRNA stabilization. J Immunol. 2013;191(2):640–649. doi:10.4049/jimmunol.1203315.
  • Sun D, Novotny M, Bulek K, et al. Treatment with IL-17 prolongs the half-life of chemokine CXCL1 mRNA via the adaptor TRAF5 and the splicing-regulatory factor SF2 (ASF). Nat Immunol. 2011;12(9):853–860. doi:10.1038/ni.2081.
  • Claudio E, Sønder SU, Saret S, et al. The adaptor protein CIKS/Act1 is essential for IL-25-mediated allergic airway inflammation. J Immunol. 2009;182(3):1617–1630. doi:10.4049/jimmunol.182.3.1617.
  • Maezawa Y, Nakajima H, Suzuki K, et al. Involvement of TNF receptor-associated factor 6 in IL-25 receptor signaling. J Immunol. 2006;176(2):1013–1018. 1950 doi:10.4049/jimmunol.176.2.1013.
  • Swaidani S, Bulek K, Kang Z, et al. The critical role of epithelial-derived Act1 in IL-17- and IL-25-mediated pulmonary inflammation. J Immunol. 2009;182(3):1631–1640. doi:10.4049/jimmunol.182.3.1631.
  • Zepp JA, Wu L, Qian W, et al. TRAF4-SMURF2-mediated DAZAP2 degradation is critical for IL-25 signaling and allergic airway inflammation. J Immunol. 2015;194(6):2826–2837. doi:10.4049/jimmunol.1402647.
  • Wu L, Zepp JA, Qian W, et al. A novel IL-25 signaling pathway through STAT5. J Immunol. 2015;194(9):4528–4534. doi:10.4049/jimmunol.1402760.
  • Shen F, Ruddy MJ, Plamondon P, Gaffen SL. Cytokines link osteoblasts and inflammation: microarray analysis of interleukin-17- and TNF-alpha-induced genes in bone cells. J Leukoc Biol. 2005;77(3):388–399. doi:10.1189/jlb.0904490.
  • Acosta-Rodriguez EV, Rivino L, Geginat J, et al. Surface phenotype and antigenic specificity of human interleukin 17-producing T helper memory cells. Nat Immunol. 2007;8(6):639–646. doi:10.1038/ni1467.
  • Reynolds JM, Lee Y-H, Shi Y, et al. Interleukin-17B antagonizes interleukin-25-mediated mucosal inflammation. Immunity. 2015;42(4):692–703. doi:10.1016/j.immuni.2015.03.008.
  • Chang SH, Reynolds JM, Pappu BP, et al. Interleukin-17C promotes Th17 cell responses and autoimmune disease via interleukin-17 receptor E. Immunity. 2011;35(4):611–621. doi:10.1016/j.immuni.2011.09.010.]
  • Johansen C, Usher PA, Kjellerup RB, et al. Characterization of the interleukin-17 isoforms and receptors in lesional psoriatic skin. Br J Dermatol. 2009;160(2):319–324. doi:10.1111/j.1365-2133.2008.08902.x.
  • Nograles KE, Zaba LC, Guttman-Yassky E, et al. Th17 cytokines interleukin (IL)-17 and IL-22 modulate distinct inflammatory and keratinocyte-response pathways. Br J Dermatol. 2008;159(5):1092–1102. doi:10.1111/j.1365-2133.2008.08769.x.
  • O’Sullivan T, Saddawi-Konefka R, Gross E, et al. Interleukin-17D mediates tumor rejection through recruitment of natural killer cells. Cell Rep. 2014;7(4):989–998. doi:10.1016/j.celrep.2014.03.073.
  • Corrigan CJ, Wang W, Meng Q, et al. Allergen-induced expression of IL-25 and IL-25 receptor in atopic asthmatic airways and late-phase cutaneous responses. J. Allergy Clin. Immunol. 2011;128(1):116–124. doi:10.1016/j.jaci.2011.03.043.
  • Fort MM, Cheung J, Yen D, et al. IL-25 Induces IL-4, IL-5, and IL-13 and Th2-Associated Pathologies In Vivo. Immunity. 2001;15(6):985–995. doi:10.1016/S1074-7613(01)00243-6.
  • Pan G, French D, Mao W, et al. Forced expression of murine IL-17E induces growth retardation, jaundice, a Th2-biased response, and multiorgan inflammation in mice. J Immunol. 2001;167(11):6559–6567. doi:10.4049/jimmunol.167.11.6559.
  • Wang Y-H, Angkasekwinai P, Lu N, et al. IL-25 augments type 2 immune responses by enhancing the expansion and functions of TSLP-DC-activated Th2 memory cells. J Exp Med. 2007;204(8):1837–1847. doi:10.1084/jem.20070406.
  • Cheng D, Xue Z, Yi L, et al. Epithelial interleukin-25 is a key mediator in Th2-high, corticosteroid-responsive asthma. Am J Respir Crit Care Med. 2014;190(6):639–648. doi:10.1164/rccm.201403-0505OC.
  • D’Andrea A, Rengaraju M, Valiante NM, et al. Production of natural killer cell stimulatory factor (interleukin 12) by peripheral blood mononuclear cells. J Exp Med. 1992;176:1387–1398.
  • Macatonia SE, Hosken NA, Litton M, et al. Dendritic cells produce IL-12 and direct the development of Th1 cells from naive CD4+ T cells. J Immunol Baltim Md 1950. 1995;154:5071–5079.
  • Schultze JL, Michalak S, Lowne J, et al. Human non-germinal center B cell interleukin (IL)-12 production is primarily regulated by T cell signals CD40 ligand, interferon gamma, and IL-10: role of B cells in the maintenance of T cell responses. J Exp Med. 1999;189(1):1–12. doi:10.1084/jem.189.1.1.
  • Jones LL, Vignali DAA. Molecular interactions within the IL-6/IL-12 cytokine/receptor superfamily. Immunol Res. 2011;51(1):5–14. doi:10.1007/s12026-011-8209-y.
  • Teng MWL, Bowman EP, McElwee JJ, et al. IL-12 and IL-23 cytokines: from discovery to targeted therapies for immune-mediated inflammatory diseases. Nat Med. 2015;21(7):719–729. doi:10.1038/nm.3895.
  • Oppmann B, Lesley R, Blom B, et al. Novel p19 protein engages IL-12p40 to form a cytokine, IL-23, with biological activities similar as well as distinct from IL-12. Immunity. 2000;13(5):715–725. doi:10.1016/S1074-7613(00)00070-4.
  • Chua AO, et al. Expression cloning of a human IL-12 receptor component. A new member of the cytokine receptor superfamily with strong homology to gp130. J Immunol Baltim Md 1950. 1994;153:128–136.
  • Parham C, Chirica M, Timans J, et al. A receptor for the heterodimeric cytokine IL-23 is composed of IL-12Rbeta1 and a novel cytokine receptor subunit, IL-23R. J Immunol. 2002;168(11):5699–5708. doi:10.4049/jimmunol.168.11.5699.
  • Presky DH, Yang H, Minetti LJ, et al. A functional interleukin 12 receptor complex is composed of two beta-type cytokine receptor subunits. Proc Natl Acad Sci USA. 1996;93(24):14002–14007. doi:10.1073/pnas.93.24.14002.
  • Jacobson NG, Szabo SJ, Weber-Nordt RM, et al. Interleukin 12 signaling in T helper type 1 (Th1) cells involves tyrosine phosphorylation of signal transducer and activator of transcription (Stat)3 and Stat4. J Exp Med. 1995;181(5):1755–1762. doi:10.1084/jem.181.5.1755.
  • Thierfelder WE, van Deursen JM, Yamamoto K, et al. Requirement for Stat4 in interleukin-12-mediated responses of natural killer and T cells. Nature. 1996;382(6587):171–174. doi:10.1038/382171a0.
  • Bacon CM, McVicar DW, Ortaldo JR, et al. Interleukin 12 (IL-12) induces tyrosine phosphorylation of JAK2 and TYK2: differential use of Janus family tyrosine kinases by IL-2 and IL-12. J Exp Med. 1995;181(1):399–404. doi:10.1084/jem.181.1.399.
  • Bacon CM, Petricoin EF, Ortaldo JR, et al. Interleukin 12 induces tyrosine phosphorylation and activation of STAT4 in human lymphocytes. Proc Natl Acad Sci USA. 1995;92(16):7307–7311. doi:10.1073/pnas.92.16.7307.
  • Visconti R, Gadina M, Chiariello M, et al. Importance of the MKK6/p38 pathway for interleukin-12-induced STAT4 serine phosphorylation and transcriptional activity. Blood. 2000;96(5):1844–1852. doi:10.1182/blood.V96.5.1844.h8001844_1844_1852.
  • Yoo JK, Cho JH, Lee SW, Sung YC. IL-12 provides proliferation and survival signals to murine CD4+ T cells through phosphatidylinositol 3-kinase/Akt signaling pathway. J Immunol. 2002;169(7):3637–3643. doi:10.4049/jimmunol.169.7.3637.
  • Ma X, Chow JM, Gri G, et al. The interleukin 12 p40 gene promoter is primed by interferon gamma in monocytic cells. J Exp Med. 1996;183(1):147–157. doi:10.1084/jem.183.1.147.
  • Cho M-L, Kang J-W, Moon Y-M, et al. STAT3 and NF-κB signal pathway is required for IL-23-mediated IL-17 production in Spontaneous arthritis animal model IL-1 receptor antagonist-deficient mice. J Immunol. 2006;176(9):5652–5661. doi:10.4049/jimmunol.176.9.5652.
  • Yang XO, Panopoulos AD, Nurieva R, et al. STAT3 regulates cytokine-mediated generation of inflammatory helper T cells. J Biol Chem. 2007;282(13):9358–9363. doi:10.1074/jbc.C600321200.
  • Cargill M, Schrodi SJ, Chang M, et al. A large-scale genetic association study confirms IL12B and leads to the identification of IL23R as psoriasis-risk genes. Am J Hum Genet. 2007;80(2):273–290. doi:10.1086/511051.
  • Cua DJ, Sherlock J, Chen Y, et al. Interleukin-23 rather than interleukin-12 is the critical cytokine for autoimmune inflammation of the brain. Nature. 2003;421(6924):744–748. doi:10.1038/nature01355.
  • Zaky DSE, El-Nahrery EMA. Role of interleukin-23 as a biomarker in rheumatoid arthritis patients and its correlation with disease activity. Int. Immunopharmacol. 2016;31:105–108. doi:10.1016/j.intimp.2015.12.011.
  • Paré A, Mailhot B, Lévesque SA, Lacroix S. Involvement of the IL-1 system in experimental autoimmune encephalomyelitis and multiple sclerosis: Breaking the vicious cycle between IL-1β and GM-CSF. Brain Behav Immun. 2017;62:1–8. doi:10.1016/j.bbi.2016.07.146.
  • Hamilton JA, Stanley ER, Burgess AW, Shadduck RK. Stimulation of macrophage plasminogen activator activity by colony-stimulating factors. J Cell Physiol. 1980;103(3):435–445. doi:10.1002/jcp.1041030309.
  • Magri G, Miyajima M, Bascones S, et al. Innate lymphoid cells integrate stromal and immunological signals to enhance antibody production by splenic marginal zone B cells. Nat Immunol. 2014;15(4):354–364. doi:10.1038/ni.2830.
  • Ponomarev ED, Shriver LP, Maresz K, et al. GM-CSF production by autoreactive T cells is required for the activation of microglial cells and the onset of experimental autoimmune encephalomyelitis. J Immunol. 2007;178(1):39–48. doi:10.4049/jimmunol.178.1.39.
  • Sawada M, Itoh Y, Suzumura A, Marunouchi T. Expression of cytokine receptors in cultured neuronal and glial cells. Neurosci Lett. 1993;160(2):131–134. doi:10.1016/0304-3940(93)90396-3.
  • Shi Y, Liu CH, Roberts AI, et al. Granulocyte-macrophage colony-stimulating factor (GM-CSF) and T-cell responses: what we do and don’t know. Cell Res. 2006;16(2):126–133. doi:10.1038/sj.cr.7310017.
  • Wheeler MA, Clark IC, Tjon EC, et al. MAFG-driven astrocytes promote CNS inflammation. Nature. 2020;578(7796):593–599. doi:10.1038/s41586-020-1999-0.
  • Burgess AW, Metcalf D. The nature and action of granulocyte-macrophage colony stimulating factors. Blood. 1980;56(6):947–958. doi:10.1182/blood.V56.6.947.bloodjournal566947.
  • Inaba K, Inaba M, Deguchi M, et al. Granulocytes, macrophages, and dendritic cells arise from a common major histocompatibility complex class II-negative progenitor in mouse bone marrow. Proc Natl Acad Sci USA. 1993;90(7):3038–3042. doi:10.1073/pnas.90.7.3038.
  • Guilliams M, De Kleer I, Henri S, et al. Alveolar macrophages develop from fetal monocytes that differentiate into long-lived cells in the first week of life via GM-CSF. J Exp Med. 2013;210(10):1977–1992. doi:10.1084/jem.20131199.
  • Shibata Y, Berclaz P-Y, Chroneos ZC, et al. GM-CSF regulates alveolar macrophage differentiation and innate immunity in the lung through PU.1. Immunity. 2001;15(4):557–567. doi:10.1016/S1074-7613(01)00218-7.
  • Rosen LB, Freeman AF, Yang LM, et al. Anti-GM-CSF autoantibodies in patients with cryptococcal meningitis. J Immunol. 2013;190(8):3959–3966. doi:10.4049/jimmunol.1202526.
  • Dougan M, Dranoff G, Dougan SK. GM-CSF, IL-3, and IL-5 family of cytokines: regulators of inflammation. Immunity. 2019;50(4):796–811. doi:10.1016/j.immuni.2019.03.022.
  • Parajuli B, Sonobe Y, Kawanokuchi J, et al. GM-CSF increases LPS-induced production of proinflammatory mediators via upregulation of TLR4 and CD14 in murine microglia. J Neuroinflammation. 2012;9:268. doi:10.1186/1742-2094-9-268.
  • Sorgi CA, Rose S, Court N, et al. GM-CSF priming drives bone marrow-derived macrophages to a pro-inflammatory pattern and downmodulates PGE2 in response to TLR2 ligands. PloS One. 2012;7(7):e40523. doi:10.1371/journal.pone.0040523.
  • Uchida K, Beck DC, Yamamoto T, et al. GM-CSF autoantibodies and neutrophil dysfunction in pulmonary alveolar proteinosis. N Engl J Med. 2007;356(6):567–579. doi:10.1056/NEJMoa062505.
  • Hansen G, Hercus TR, McClure BJ, et al. The structure of the GM-CSF receptor complex reveals a distinct mode of cytokine receptor activation. Cell. 2008;134(3):496–507. doi:10.1016/j.cell.2008.05.053.
  • Brizzi MF, Zini MG, Aronica MG, et al. Convergence of signaling by interleukin-3, granulocyte-macrophage colony-stimulating factor, and mast cell growth factor on JAK2 tyrosine kinase. J Biol Chem. 1994;269(50):31680–31684. doi:10.1016/S0021-9258(18)31749-6.
  • Broughton SE, Hercus TR, Nero TL, et al. Conformational changes in the GM-CSF receptor suggest a molecular mechanism for affinity conversion and receptor signaling. Structure. 2016;24(8):1271–1281. doi:10.1016/j.str.2016.05.017.
  • Guthridge MA, Stomski FC, Thomas D, et al. Mechanism of activation of the GM-CSF, IL-3, and IL-5 family of receptors. Stem Cells. 1998;16(5):301–313. doi:10.1002/stem.160301.
  • Lehtonen A, Matikainen S, Miettinen M, Julkunen I. Granulocyte-macrophage colony-stimulating factor (GM-CSF)-induced STAT5 activation and target-gene expression during human monocyte/macrophage differentiation. J Leukoc Biol. 2002;71(3):511–519.
  • Cook AD, Lee M-C, Saleh R, et al. TNF and granulocyte macrophage-colony stimulating factor interdependence mediates inflammation via CCL17. JCI Insight. 2018;3(6):e99249. doi:10.1172/jci.insight.99249.
  • Bozinovski S, Jones JE, Vlahos R, Hamilton JA, Anderson GP. Granulocyte/Macrophage-Colony-Stimulating Factor (GM-CSF) regulates lung innate immunity to lipopolysaccharide through Akt/Erk activation of NFκB and AP-1 in Vivo. J Biol Chem. 2002;277(45):42808–42814. doi:10.1074/jbc.M207840200.
  • Klein SL, Flanagan KL. Sex differences in immune responses. Nat Rev Immunol. 2016;16(10):626–638. doi:10.1038/nri.2016.90.
  • Mousavi MJ, Mahmoudi M, Ghotloo S. Escape from X chromosome inactivation and female bias of autoimmune diseases. Mol Med. 2020;26(1):127. doi:10.1186/s10020-020-00256-1.
  • Oghumu S, Varikuti S, Stock JC, et al. Cutting edge: CXCR3 escapes X Chromosome Inactivation in T Cells during Infection: Potential Implications for Sex Differences in Immune Responses. J Immunol. 2019;203(4):789–794. doi:10.4049/jimmunol.1800931.
  • Brown MA, Su MA. An Inconvenient Variable: Sex Hormones and Their Impact on T Cell Responses. JI. 2019;202(7):1927–1933. doi:10.4049/jimmunol.1801403.
  • Cleve A, et al. Pharmacology and clinical use of sex steroid hormone receptor modulators. Handb. Exp. Pharmacol. 2012;543–587. doi:10.1007/978-3-642-30726-3_24.
  • Sever R, Glass CK. Signaling by nuclear receptors. Cold Spring Harb Perspect Biol. 2013;5(3):a016709–a016709. doi:10.1101/cshperspect.a016709.
  • Fox HS, Bond BL, Parslow TG. Estrogen regulates the IFN-gamma promoter. J. Immunol. Baltim. Md 1950. 1991;146:4362–4367.
  • Kissick HT, Sanda MG, Dunn LK, et al. Androgens alter T-cell immunity by inhibiting T-helper 1 differentiation. Proc Natl Acad Sci U S A. 2014;111(27):9887–9892. doi:10.1073/pnas.1402468111.
  • Liva SM, Voskuhl RR. Testosterone acts directly on CD4+ T lymphocytes to increase IL-10 production. J Immunol. 2001;167(4):2060–2067. doi:10.4049/jimmunol.167.4.2060.
  • Kumar N, Shan LX, Hardy MP, Bardin CW, Sundaram K. Mechanism of androgen-induced thymolysis in rats. Endocrinology. 1995;136(11):4887–4893. doi:10.1210/endo.136.11.7588221.
  • Altuwaijri S, Chuang K-H, Lai K-P, et al. Susceptibility to autoimmunity and B cell resistance to apoptosis in mice lacking androgen receptor in B cells. Mol. Endocrinol. Baltim. Md. 2009;23(4):444–453. doi:10.1210/me.2008-0106.
  • Kadel S, Kovats S. Sex Hormones Regulate Innate Immune Cells and Promote Sex Differences in Respiratory Virus Infection. Front Immunol. 2018;9:1653. doi:10.3389/fimmu.2018.01653.
  • Zhang MA, Rego D, Moshkova M, et al. Peroxisome proliferator-activated receptor (PPAR)α and -γ regulate IFNγ and IL-17A production by human T cells in a sex-specific way. Proc. Natl. Acad. Sci. U. S. A. 2012;109(24):9505–9510. doi:10.1073/pnas.1118458109.
  • Billi AC, Kahlenberg JM, Gudjonsson JE. Sex bias in autoimmunity. Curr Opin Rheumatol. 2019;31(1):53–61. doi:10.1097/BOR.0000000000000564.
  • Straub RH. The complex role of estrogens in inflammation. Endocr Rev. 2007;28(5):521–574. doi:10.1210/er.2007-0001.
  • Phiel KL, Henderson RA, Adelman SJ, Elloso MM. Differential estrogen receptor gene expression in human peripheral blood mononuclear cell populations. Immunol Lett. 2005;97(1):107–113. doi:10.1016/j.imlet.2004.10.007.
  • Kovats S. Estrogen receptors regulate innate immune cells and signaling pathways. Cell Immunol. 2015;294(2):63–69. doi:10.1016/j.cellimm.2015.01.018.
  • Polanczyk MJ, Hopke C, Huan J, Vandenbark AA, Offner H. Enhanced FoxP3 expression and Treg cell function in pregnant and estrogen-treated mice. J Neuroimmunol. 2005;170(1-2):85–92. doi:10.1016/j.jneuroim.2005.08.023.
  • Tai P, Wang J, Jin H, et al. Induction of regulatory T cells by physiological level estrogen. J Cell Physiol. 2008;214(2):456–464. doi:10.1002/jcp.21221.
  • Bereshchenko O, Bruscoli S, Riccardi C. Glucocorticoids, Sex Hormones, and Immunity. Front Immunol. 2018;9:1332. doi:10.3389/fimmu.2018.01332.
  • Dragin N, Bismuth J, Cizeron-Clairac G, et al. Estrogen-mediated downregulation of AIRE influences sexual dimorphism in autoimmune diseases. J Clin Invest. 2016;126(4):1525–1537. doi:10.1172/JCI81894.
  • Marttila S, Jylhävä J, Nevalainen T, et al. Transcriptional analysis reveals gender-specific changes in the aging of the human immune system. PloS One. 2013;8(6):e66229. doi:10.1371/journal.pone.0066229.
  • Olsen NJ, Kovacs WJ. Gonadal steroids and immunity. Endocr Rev. 1996;17(4):369–384. doi:10.1210/edrv-17-4-369.
  • Dosiou C, Hamilton AE, Pang Y, et al. Expression of membrane progesterone receptors on human T lymphocytes and Jurkat cells and activation of G-proteins by progesterone. J Endocrinol. 2008;196(1):67–77. doi:10.1677/JOE-07-0317.
  • Teilmann SC, Clement CA, Thorup J, Byskov AG, Christensen ST. Expression and localization of the progesterone receptor in mouse and human reproductive organs. J Endocrinol. 2006;191(3):525–535. doi:10.1677/joe.1.06565.
  • Hall OJ, Klein SL. Progesterone-based compounds affect immune responses and susceptibility to infections at diverse mucosal sites. Mucosal Immunol. 2017;10(5):1097–1107. doi:10.1038/mi.2017.35.
  • Tan IJ, Peeva E, Zandman-Goddard G. Hormonal modulation of the immune system - A spotlight on the role of progestogens. Autoimmun Rev. 2015;14(6):536–542. doi:10.1016/j.autrev.2015.02.004.
  • Deese J, Masson L, Miller W, et al. Injectable Progestin-Only Contraception is Associated With Increased Levels of Pro-Inflammatory Cytokines in the Female Genital Tract. Am J Reprod Immunol. 2015;74(4):357–367. doi:10.1111/aji.12415.
  • Hughes GC. Progesterone and autoimmune disease. Autoimmun Rev. 2012;11(6-7):A502–514. doi:10.1016/j.autrev.2011.12.003.
  • Polikarpova AV, Levina IS, Sigai NV, et al. Immunomodulatory effects of progesterone and selective ligands of membrane progesterone receptors. Steroids. 2019;145:5–18. doi:10.1016/j.steroids.2019.02.009.
  • Piccinni MP, et al. Progesterone favors the development of human T helper cells producing Th2-type cytokines and promotes both IL-4 production and membrane CD30 expression in established Th1 cell clones. J. Immunol. Baltim. Md. 1950; 155:128–133. 1995).
  • Foo YZ, Nakagawa S, Rhodes G, Simmons LW. The effects of sex hormones on immune function: a meta-analysis. Biol Rev Camb Philos Soc. 2017;92(1):551–571. doi:10.1111/brv.12243.
  • Guevara Patiño JA, Marino MW, Ivanov VN, Nikolich-Zugich J. Sex steroids induce apoptosis of CD8 + CD4+ double-positive thymocytes via TNF-alpha. Eur J Immunol. 2000;30(9):2586–2592. doi:10.1002/1521-4141(200009)30:9<2586::AID-IMMU2586>3.0.CO;2-L.
  • Zhu M-L, Bakhru P, Conley B, et al. Sex bias in CNS autoimmune disease mediated by androgen control of autoimmune regulator. Nat Commun. 2016;7:11350. doi:10.1038/ncomms11350.
  • Velardi E, Tsai JJ, Holland AM, et al. Sex steroid blockade enhances thymopoiesis by modulating Notch signaling. J Exp Med. 2014;211(12):2341–2349. doi:10.1084/jem.20131289.
  • Doshi A, Chataway J. Multiple sclerosis, a treatable disease. Clin Med (Lond)). 2016;16(Suppl 6):s53–s59. doi:10.7861/clinmedicine.16-6-s53.
  • Owens GM. Economic burden of multiple sclerosis and the role of managed sare organizations in multiple sclerosis management. Am J Manag Care. 2016;22(6 Suppl):S151–S158.
  • Stüve O, Marra CM, Jerome KR, et al. Immune surveillance in multiple sclerosis patients treated with natalizumab. Ann Neurol. 2006;59(5):743–747. doi:10.1002/ana.20858.
  • Rep MHG, Schrijver HM, van Lopik T, et al. Interferon (IFN)-beta treatment enhances CD95 and interleukin 10 expression but reduces interferon-gamma producing T cells in MS patients. J. Neuroimmunol. 1999;96(1):92–100. doi:10.1016/S0165-5728(98)00271-9.
  • Schreiner B, Mitsdoerffer M, Kieseier BC, et al. Interferon-beta enhances monocyte and dendritic cell expression of B7-H1 (PD-L1), a strong inhibitor of autologous T-cell activation: relevance for the immune modulatory effect in multiple sclerosis. J. Neuroimmunol. 2004;155(1-2):172–182. doi:10.1016/j.jneuroim.2004.06.013.
  • Duda PW, Schmied MC, Cook SL, Krieger JI, Hafler DA. Glatiramer acetate (Copaxone) induces degenerate, Th2-polarized immune responses in patients with multiple sclerosis. J Clin Invest. 2000;105(7):967–976. doi:10.1172/JCI8970.
  • Sipe JC, Romine JS, Koziol JA, et al. Development of cladribine treatment in multiple sclerosis. Mult Scler. 1996;1(6):343–347. doi:10.1177/135245859600100612.
  • Stelmasiak Z, Solski J, Nowicki J, et al. Effect of parenteral cladribine on relapse rates in patients with relapsing forms of multiple sclerosis: results of a 2-year, double-blind, placebo-controlled, crossover study. Mult Scler. 2009;15(6):767–770. doi:10.1177/1352458509103610.
  • Karman J, Ling C, Sandor M, Fabry Z. Initiation of Immune Responses in Brain Is Promoted by Local Dendritic Cells. J Immunol. 2004;173(4):2353–2361. doi:10.4049/jimmunol.173.4.2353.
  • Prodinger C, Bunse J, Krüger M, et al. CD11c-expressing cells reside in the juxtavascular parenchyma and extend processes into the glia limitans of the mouse nervous system. Acta Neuropathol. 2011;121(4):445–458. doi:10.1007/s00401-010-0774-y.
  • Mohammad MG, Tsai VWW, Ruitenberg MJ, et al. Immune cell trafficking from the brain maintains CNS immune tolerance. J Clin Invest. 2014;124(3):1228–1241. doi:10.1172/JCI71544.
  • Zhang Y, Han J, Wu M, et al. Toll-Like Receptor 4 Promotes Th17 Lymphocyte Infiltration Via CCL25/CCR9 in Pathogenesis of Experimental Autoimmune Encephalomyelitis. J Neuroimmune Pharmacol. 2019;14(3):493–502. doi:10.1007/s11481-019-09854-1.
  • Larochelle C, Cayrol R, Kebir H, et al. Melanoma cell adhesion molecule identifies encephalitogenic T lymphocytes and promotes their recruitment to the central nervous system. Brain. 2012;135(Pt 10):2906–2924. doi:10.1093/brain/aws212.
  • Breuer J, Korpos E, Hannocks M-J, et al. Blockade of MCAM/CD146 impedes CNS infiltration of T cells over the choroid plexus. J Neuroinflammation. 2018;15(1):236. doi:10.1186/s12974-018-1276-4.
  • Lutz SE, Smith JR, Kim DH, et al. Caveolin1 Is Required for Th1 Cell Infiltration, but Not Tight Junction Remodeling, at the Blood-Brain Barrier in Autoimmune Neuroinflammation. Cell Rep. 2017;21(8):2104–2117. doi:10.1016/j.celrep.2017.10.094.
  • Reboldi A, Coisne C, Baumjohann D, et al. C-C chemokine receptor 6-regulated entry of TH-17 cells into the CNS through the choroid plexus is required for the initiation of EAE. Nat Immunol. 2009;10(5):514–523. doi:10.1038/ni.1716.
  • Kebir H, Kreymborg K, Ifergan I, et al. Human TH17 lymphocytes promote blood-brain barrier disruption and central nervous system inflammation. Nat Med. 2007;13(10):1173–1175. doi:10.1038/nm1651.
  • Kessenbrock K, Dau T, Jenne DE. Tailor-made inflammation: how neutrophil serine proteases modulate the inflammatory response. J Mol Med (Berl)). 2011;89(1):23–28. doi:10.1007/s00109-010-0677-3.
  • Balasa R, Bianca C, Septimiu V, et al. The Matrix Metalloproteinases Panel in Multiple Sclerosis Patients Treated with Natalizumab: A Possible Answer to Natalizumab Non- Responders. CNS Neurol Disord Drug Targets. 2018;17(6):464–472. doi:10.2174/1871527317666180703102536.
  • Huppert J, Closhen D, Croxford A, et al. Cellular mechanisms of IL-17-induced blood-brain barrier disruption. Faseb J. 2010;24(4):1023–1034. doi:10.1096/fj.09-141978.
  • Ni C, Wang C, Zhang J, et al. Interferon-γ safeguards blood-brain barrier during experimental autoimmune encephalomyelitis. Am J Pathol. 2014;184(12):3308–3320. doi:10.1016/j.ajpath.2014.08.019.
  • Bartholomäus I, Kawakami N, Odoardi F, et al. Effector T cell interactions with meningeal vascular structures in nascent autoimmune CNS lesions. Nature. 2009;462(7269):94–98. doi:10.1038/nature08478.
  • Juedes AE, Ruddle NH. Resident and infiltrating central nervous system APCs regulate the emergence and resolution of experimental autoimmune encephalomyelitis. J Immunol. 2001;166(8):5168–5175. doi:10.4049/jimmunol.166.8.5168.
  • Pierson ER, Stromnes IM, Goverman JM. B cells promote induction of experimental autoimmune encephalomyelitis by facilitating reactivation of T cells in the central nervous system. J Immunol. 2014;192(3):929–939. doi:10.4049/jimmunol.1302171.
  • Greter M, Heppner FL, Lemos MP, et al. Dendritic cells permit immune invasion of the CNS in an animal model of multiple sclerosis. Nat Med. 2005;11(3):328–334. doi:10.1038/nm1197.
  • Karman J, Chu HH, Co DO, et al. Dendritic cells amplify T cell-mediated immune responses in the central nervous system. J Immunol. 2006;177(11):7750–7760. doi:10.4049/jimmunol.177.11.7750.
  • Bailey SL, Schreiner B, McMahon EJ, Miller SD. CNS myeloid DCs presenting endogenous myelin peptides ‘preferentially’ polarize CD4+ TH-17 cells in relapsing EAE. Nat Immunol. 2007;8(2):172–180. doi:10.1038/ni1430.
  • Miller SD, McMahon EJ, Schreiner B, Bailey SL. Antigen presentation in the CNS by myeloid dendritic cells drives progression of relapsing experimental autoimmune encephalomyelitis. Ann N Y Acad Sci. 2007;1103:179–191. doi:10.1196/annals.1394.023.
  • Paterka M, Siffrin V, Voss JO, et al. Gatekeeper role of brain antigen-presenting CD11c + cells in neuroinflammation. Embo J. 2016;35(1):89–101. doi:10.15252/embj.201591488.
  • Li Z, He C, Zhang J, et al. P2Y6 deficiency enhances dendritic cell-mediated Th1/Th17 differentiation and aggravates experimental autoimmune encephalomyelitis. JI. 2020;205(2):387–397. doi:10.4049/jimmunol.1900916.
  • Paterka M, Voss JO, Werr J, et al. Dendritic cells tip the balance towards induction of regulatory T cells upon priming in experimental autoimmune encephalomyelitis. J Autoimmun. 2017;76:108–114. doi:10.1016/j.jaut.2016.09.008.
  • Lin C-C, Bradstreet TR, Schwarzkopf EA, et al. IL-1-induced Bhlhe40 identifies pathogenic T helper cells in a model of autoimmune neuroinflammation. J Exp Med. 2016;213(2):251–271. doi:10.1084/jem.20150568.
  • Emming S, Bianchi N, Polletti S, et al. A molecular network regulating the proinflammatory phenotype of human memory T lymphocytes. Nat Immunol. 2020;21(4):388–399. doi:10.1038/s41590-020-0622-8.
  • Lin C-C, et al. Bhlhe40 controls cytokine production by T cells and is essential for pathogenicity in autoimmune neuroinflammation. Nat. Commun. 2014;5:3551.
  • Yu F, Sharma S, Jankovic D, et al. The transcription factor Bhlhe40 is a switch of inflammatory versus antiinflammatory Th1 cell fate determination. J Exp Med. 2018;215(7):1813–1821. doi:10.1084/jem.20170155.
  • Lock C, Hermans G, Pedotti R, et al. Gene-microarray analysis of multiple sclerosis lesions yields new targets validated in autoimmune encephalomyelitis. Nat Med. 2002;8(5):500–508. doi:10.1038/nm0502-500.
  • Stromnes IM, Goverman JM. Passive induction of experimental allergic encephalomyelitis. Nat Protoc. 2006;1(4):1952–1960. doi:10.1038/nprot.2006.284.
  • O’Connor RA, et al. Cutting edge: Th1 cells facilitate the entry of Th17 cells to the central nervous system during experimental autoimmune encephalomyelitis. J. Immunol. Baltim. Md 1950. 2008;181:3750–3754.
  • Panitch HS, Hirsch RL, Haley AS, Johnson KP. Exacerbations of multiple sclerosis in patients treated with gamma interferon. Lancet Lond. Engl. 1987;329(8538):893–895. doi:10.1016/S0140-6736(87)92863-7.
  • Carvalheiro T, Rafael-Vidal C, Malvar-Fernandez B, et al. Semaphorin4A-Plexin D1 Axis induces Th2 and Th17 while represses Th1 skewing in an autocrine manner. IJMS. 2020;21(18):6965. doi:10.3390/ijms21186965.
  • Nakatsuji Y, Okuno T, Moriya M, et al. Elevation of Sema4A implicates Th cell skewing and the efficacy of IFN-β Therapy in multiple sclerosis. JI. 2012;188(10):4858–4865. doi:10.4049/jimmunol.1102023.
  • Lublin FD, Knobler RL, Kalman B, et al. Monoclonal anti-gamma interferon antibodies enhance experimental allergic encephalomyelitis. Autoimmunity. 1993;16(4):267–274. doi:10.3109/08916939309014645.
  • Ferber IA, et al. Mice with a disrupted IFN-gamma gene are susceptible to the induction of experimental autoimmune encephalomyelitis (EAE). J Immunol Baltim Md 1950. 1996;156:5–7.
  • Popko B, Baerwald KD. Oligodendroglial response to the immune cytokine interferon gamma. Neurochem Res. 1999;24(2):331–338. doi:10.1023/A:1022586726510.
  • Prajeeth CK, Löhr K, Floess S, et al. Effector molecules released by Th1 but not Th17 cells drive an M1 response in microglia. Brain Behav Immun. 2014;37:248–259. doi:10.1016/j.bbi.2014.01.001.
  • Miller SD, Vanderlugt CL, Lenschow DJ, et al. Blockade of CD28/B7-1 interaction prevents epitope spreading and clinical relapses of murine EAE. Immunity. 1995;3(6):739–745. doi:10.1016/1074-7613(95)90063-2.
  • Kroenke MA, Carlson TJ, Andjelkovic AV, Segal BM. IL-12- and IL-23-modulated T cells induce distinct types of EAE based on histology, CNS chemokine profile, and response to cytokine inhibition. J Exp Med. 2008;205(7):1535–1541. doi:10.1084/jem.20080159.
  • King IL, Dickendesher TL, Segal BM. Circulating Ly-6C + myeloid precursors migrate to the CNS and play a pathogenic role during autoimmune demyelinating disease. Blood. 2009;113(14):3190–3197. doi:10.1182/blood-2008-07-168575.
  • Ko H-J, Brady JL, Ryg-Cornejo V, et al. GM-CSF-responsive monocyte-derived dendritic cells are pivotal in Th17 pathogenesis. J Immunol. 2014;192(5):2202–2209. doi:10.4049/jimmunol.1302040.
  • Croxford AL, Lanzinger M, Hartmann FJ, et al. The cytokine GM-CSF drives the inflammatory signature of CCR2+ monocytes and licenses autoimmunity. Immunity. 2015;43(3):502–514. doi:10.1016/j.immuni.2015.08.010.
  • Spath S, Komuczki J, Hermann M, et al. Dysregulation of the cytokine GM-CSF induces spontaneous phagocyte invasion and immunopathology in the central nervous system. Immunity. 2017;46(2):245–260. doi:10.1016/j.immuni.2017.01.007.
  • Schinocca C, Rizzo C, Fasano S, et al. Role of the IL-23/IL-17 pathway in rheumatic diseases: an overview. Front Immunol. 2021;12. doi:10.3389/fimmu.2021.637829.
  • Al-Saffar N, Khwaja HA, Kadoya Y, Revell PA. Assessment of the role of GM-CSF in the cellular transformation and the development of erosive lesions around orthopaedic implants. Am J Clin Pathol. 1996;105(5):628–639. doi:10.1093/ajcp/105.5.628.
  • McQualter JL, Darwiche R, Ewing C, et al. Granulocyte macrophage colony-stimulating factor: a new putative therapeutic target in multiple sclerosis. J Exp Med. 2001;194(7):873–882. doi:10.1084/jem.194.7.873.
  • Duhen R, Glatigny S, Arbelaez CA, et al. Cutting edge: the pathogenicity of IFN-γ–producing Th17 cells is independent of T-bet. JI. 2013;190(9):4478–4482. doi:10.4049/jimmunol.1203172.
  • Ganor Y, Teichberg VI, Levite M. TCR activation eliminates glutamate receptor GluR3 from the cell surface of normal human T Cells, via an autocrine/paracrine granzyme B-mediated proteolytic cleavage. J Immunol. 2007;178(2):683–692. doi:10.4049/jimmunol.178.2.683.
  • Poholek CH, et al. Noncanonical STAT3 activity sustains pathogenic Th17 proliferation and cytokine response to antigen. J Exp Med. 2020;217:e20191761.
  • Sen S, He Z, Ghosh S, et al. PRMT1 plays a critical role in Th17 differentiation by regulating reciprocal recruitment of STAT3 and STAT5. J Immunol. 2018;201(2):440–450. doi:10.4049/jimmunol.1701654.
  • Cho JJ, Xu Z, Parthasarathy U, et al. Hectd3 promotes pathogenic Th17 lineage through Stat3 activation and Malt1 signaling in neuroinflammation. Nat Commun. 2019;10(1):701. doi:10.1038/s41467-019-08605-3.
  • Chitrakar A, Budda SA, Henderson JG, Axtell RC, Zenewicz LA. E3 ubiquitin ligase Von Hippel-Lindau protein promotes Th17 differentiation. JI. 2020;205(4):1009–1023. doi:10.4049/jimmunol.2000243.
  • Lee J-Y, Hall JA, Kroehling L, et al. Serum amyloid A proteins induce pathogenic Th17 cells and promote inflammatory disease. Cell. 2020;180(1):79–91.e16. doi:10.1016/j.cell.2019.11.026.
  • Angiari S, Runtsch MC, Sutton CE, et al. Pharmacological activation of pyruvate kinase M2 inhibits CD4+ T cell pathogenicity and suppresses autoimmunity. Cell Metab. 2020;31(2):391–405.e8. doi:10.1016/j.cmet.2019.10.015.]
  • Damasceno LEA, et al. PKM2 promotes Th17 cell differentiation and autoimmune inflammation by fine-tuning STAT3 activation. J. Exp. Med. 2020;217.
  • Brenner MB, McLean J, Dialynas DP, et al. Identification of a putative second T-cell receptor. Nature. 1986;322(6075):145–149. doi:10.1038/322145a0.
  • Martin B, Hirota K, Cua DJ, Stockinger B, Veldhoen M. Interleukin-17-producing gammadelta T cells selectively expand in response to pathogen products and environmental signals. Immunity. 2009;31(2):321–330. doi:10.1016/j.immuni.2009.06.020.
  • Lafont V, Liautard J, Liautard JP, Favero J. Production of TNF-alpha by human V gamma 9V delta 2 T cells via engagement of Fc gamma RIIIA, the low affinity type 3 receptor for the Fc portion of IgG, expressed upon TCR activation by nonpeptidic antigen. J Immunol. 2001;166(12):7190–7199. doi:10.4049/jimmunol.166.12.7190.
  • Lockhart E, Green AM, Flynn JL. IL-17 production is dominated by gammadelta T cells rather than CD4 T cells during Mycobacterium tuberculosis infection. J Immunol. 2006;177(7):4662–4669. doi:10.4049/jimmunol.177.7.4662.
  • Rhodes KA, Andrew EM, Newton DJ, Tramonti D, Carding SR. A subset of IL-10-producing gammadelta T cells protect the liver from Listeria-elicited, CD8(+) T cell-mediated injury. Eur J Immunol. 2008;38(8):2274–2283. doi:10.1002/eji.200838354.
  • Sutton CE, Lalor SJ, Sweeney CM, et al. Interleukin-1 and IL-23 induce innate IL-17 production from gammadelta T cells, amplifying Th17 responses and autoimmunity. Immunity. 2009;31(2):331–341. doi:10.1016/j.immuni.2009.08.001.
  • Lukens JR, Barr MJ, Chaplin DD, Chi H, Kanneganti T-D. Inflammasome-derived IL-1β regulates the production of GM-CSF by CD4(+) T cells and γδ T cells. J Immunol. 2012;188(7):3107–3115. doi:10.4049/jimmunol.1103308.
  • Zeine R, Pon R, Ladiwala U, et al. Mechanism of gammadelta T cell-induced human oligodendrocyte cytotoxicity: relevance to multiple sclerosis. J. Neuroimmunol. 1998;87(1-2):49–61. doi:10.1016/S0165-5728(98)00047-2.
  • Petermann F, Rothhammer V, Claussen MC, et al. γδ T cells enhance autoimmunity by restraining regulatory T cell responses via an interleukin-23-dependent mechanism. Immunity. 2010;33(3):351–363. doi:10.1016/j.immuni.2010.08.013.
  • Kawanokuchi J, Shimizu K, Nitta A, et al. Production and functions of IL-17 in microglia. J Neuroimmunol. 2008;194(1-2):54–61. doi:10.1016/j.jneuroim.2007.11.006.
  • McGinley AM, Sutton CE, Edwards SC, et al. Interleukin-17A serves a priming role in autoimmunity by recruiting IL-1β-producing myeloid cells that promote pathogenic T cells. Immunity. 2020;52(2):342–356.e6. doi:10.1016/j.immuni.2020.01.002.
  • Trajkovic V, Stosic-Grujicic S, Samardzic T, et al. Interleukin-17 stimulates inducible nitric oxide synthase activation in rodent astrocytes. J Neuroimmunol. 2001;119(2):183–191. doi:10.1016/S0165-5728(01)00391-5.
  • Ma X, Reynolds SL, Baker BJ, et al. IL-17 enhancement of the IL-6 signaling cascade in astrocytes. J Immunol. 2010;184(9):4898–4906. doi:10.4049/jimmunol.1000142.
  • Shan K, et al. IL-17-triggered downregulation of miR-497 results in high HIF-1α expression and consequent IL-1β and IL-6 production by astrocytes in EAE mice. Cell Mol Immunol. 2017; doi:10.1038/cmi.2017.12.
  • Hauser SL, Bhan AK, Gilles F, et al. Immunohistochemical analysis of the cellular infiltrate in multiple sclerosis lesions. Ann Neurol. 1986;19(6):578–587. doi:10.1002/ana.410190610.
  • Babbe H, Roers A, Waisman A, et al. Clonal expansions of CD8(+) T cells dominate the T cell infiltrate in active multiple sclerosis lesions as shown by micromanipulation and single cell polymerase chain reaction. J Exp Med. 2000;192(3):393–404. doi:10.1084/jem.192.3.393.
  • Jilek S, Schluep M, Rossetti AO, et al. CSF enrichment of highly differentiated CD8+ T cells in early multiple sclerosis. Clin Immunol. 2007;123(1):105–113. doi:10.1016/j.clim.2006.11.004.
  • Ifergan I, Kebir H, Alvarez JI, et al. Central nervous system recruitment of effector memory CD8+ T lymphocytes during neuroinflammation is dependent on α4 integrin. Brain. 2011;134(Pt 12):3560–3577. doi:10.1093/brain/awr268.
  • Malmeström C, Lycke J, Haghighi S, et al. Relapses in multiple sclerosis are associated with increased CD8+ T-cell mediated cytotoxicity in CSF. J Neuroimmunol. 2008;196(1-2):159–165. doi:10.1016/j.jneuroim.2008.03.001.
  • Polman CH, O’Connor PW, Havrdova E, et al. A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med. 2006;354(9):899–910. doi:10.1056/NEJMoa044397.
  • Ransohoff RM, Estes ML. Astrocyte expression of major histocompatibility complex gene products in multiple sclerosis brain tissue obtained by stereotactic biopsy. Arch Neurol. 1991;48(12):1244–1246. doi:10.1001/archneur.1991.00530240048017.
  • Gobin SJP, Montagne L, Van Zutphen M, et al. Upregulation of transcription factors controlling MHC expression in multiple sclerosis lesions. Glia. 2001;36(1):68–77. doi:10.1002/glia.1096.
  • Höftberger R, Aboul-Enein F, Brueck W, et al. Expression of major histocompatibility complex class I molecules on the different cell types in multiple sclerosis lesions. Brain Pathol. 2004;14(1):43–50. doi:10.1111/j.1750-3639.2004.tb00496.x.
  • Sauer BM, Schmalstieg WF, Howe CL. Axons are injured by antigen-specific CD8(+) T cells through a MHC class I- and granzyme B-dependent mechanism. Neurobiol Dis. 2013;59:194–205. doi:10.1016/j.nbd.2013.07.010.
  • Pouly S, Becher B, Blain M, Antel JP. Interferon-gamma modulates human oligodendrocyte susceptibility to Fas-mediated apoptosis. J Neuropathol Exp Neurol. 2000;59(4):280–286. doi:10.1093/jnen/59.4.280.
  • Medana I, Li Z, Flügel A, et al. Fas ligand (CD95L) protects neurons against perforin-mediated T lymphocyte cytotoxicity. J Immunol. 2001;167(2):674–681. doi:10.4049/jimmunol.167.2.674.
  • Sasaki K, Bean A, Shah S, et al. Relapsing-remitting central nervous system autoimmunity mediated by GFAP-specific CD8 T cells. J Immunol. 2014;192(7):3029–3042. doi:10.4049/jimmunol.1302911.
  • Machado-Santos J, Saji E, Tröscher AR, et al. The compartmentalized inflammatory response in the multiple sclerosis brain is composed of tissue-resident CD8+ T lymphocytes and B cells. Brain. 2018;141(7):2066–2082. doi:10.1093/brain/awy151.
  • Saligrama N, Zhao F, Sikora MJ, et al. Opposing T cell responses in experimental autoimmune encephalomyelitis. Nature. 2019;572(7770):481–487. doi:10.1038/s41586-019-1467-x.
  • Peng Y, Zhu F-Z, Chen Z-X, et al. Characterization of myelin oligodendrocyte glycoprotein (MOG)35-55-specific CD8+ T cells in experimental autoimmune encephalomyelitis. Chin Med J (Engl). 2019;132(24):2934–2940. doi:10.1097/CM9.0000000000000551.
  • Wagner CA, Roqué PJ, Mileur TR, Liggitt D, Goverman JM. Myelin-specific CD8+ T cells exacerbate brain inflammation in CNS autoimmunity. J. Clin. Invest. 2019;130(1):203–213. doi:10.1172/JCI132531.
  • Fritzsching B, Haas J, König F, et al. Intracerebral human regulatory T Cells: analysis of CD4+ CD25+ FOXP3+ T cells in brain lesions and cerebrospinal fluid of multiple sclerosis patients. PLoS ONE. 2011;6(3):e17988. doi:10.1371/journal.pone.0017988.
  • Othy S, Jairaman A, Dynes JL, et al. Regulatory T cells suppress Th17 cell Ca2+ signaling in the spinal cord during murine autoimmune neuroinflammation. Proc Natl Acad Sci USA. 2020;117(33):20088–20099. doi:10.1073/pnas.2006895117.
  • Putheti P, Soderstrom M, Link H, Huang Y-M. Effect of glatiramer acetate (Copaxone) on CD4 + CD25high T regulatory cells and their IL-10 production in multiple sclerosis. J. Neuroimmunol. 2003;144(1-2):125–131. doi:10.1016/j.jneuroim.2003.08.001.
  • Viglietta V, Baecher-Allan C, Weiner HL, Hafler DA. Loss of functional suppression by CD4 + CD25+ regulatory T cells in patients with multiple sclerosis. J Exp Med. 2004;199(7):971–979. doi:10.1084/jem.20031579.
  • Kumar M, Putzki N, Limmroth V, et al. CD4 + CD25 + FoxP3+ T lymphocytes fail to suppress myelin basic protein-induced proliferation in patients with multiple sclerosis. J. Neuroimmunol. 2006;180(1-2):178–184. doi:10.1016/j.jneuroim.2006.08.003.
  • Venken K, Hellings N, Broekmans T, et al. Natural naive CD4 + CD25 + CD127low regulatory T cell (Treg) development and function are disturbed in multiple sclerosis patients: recovery of memory Treg homeostasis during disease progression. J Immunol. 2008;180(9):6411–6420. 1950 doi:10.4049/jimmunol.180.9.6411.
  • Balint B, Haas J, Schwarz A, et al. T-cell homeostasis in pediatric multiple sclerosis: Old cells in young patients. Neurology. 2013;81(9):784–792. doi:10.1212/WNL.0b013e3182a2ce0e.
  • Filippi M, et al. Multiple sclerosis. Nat Rev Dis Primer. 2018;4:43.
  • Nicot A. Gender and sex hormones in multiple sclerosis pathology and therapy. Front Biosci (Landmark Ed)). 2009;14:4477–4515. doi:10.2741/3543.
  • Bove R, Chitnis T. Sexual disparities in the incidence and course of MS. Clin Immunol Orlando Fla. 2013;149(2):201–210. doi:10.1016/j.clim.2013.03.005.
  • Desai MK, Brinton RD. Autoimmune disease in women: endocrine transition and risk across the lifespan. Front Endocrinol (Lausanne). 2019;10:265. doi:10.3389/fendo.2019.00265.
  • Wiedrick J, Meza-Romero R, Gerstner G, et al. Sex differences in EAE reveal common and distinct cellular and molecular components. Cell Immunol. 2021;359:104242. doi:10.1016/j.cellimm.2020.104242.
  • Haghmorad D, Amini AA, Mahmoudi MB, et al. Pregnancy level of estrogen attenuates experimental autoimmune encephalomyelitis in both ovariectomized and pregnant C57BL/6 mice through expansion of Treg and Th2 cells. J Neuroimmunol. 2014;277(1-2):85–95. doi:10.1016/j.jneuroim.2014.10.004.
  • Spanier JA, Nashold FE, Mayne CG, Nelson CD, Hayes CE. Vitamin D and estrogen synergy in Vdr-expressing CD4(+) T cells is essential to induce Helios(+)FoxP3(+) T cells and prevent autoimmune demyelinating disease. J Neuroimmunol. 2015;286:48–58. doi:10.1016/j.jneuroim.2015.06.015.
  • Russi AE, Ebel ME, Yang Y, Brown MA. Male-specific IL-33 expression regulates sex-dimorphic EAE susceptibility. Proc Natl Acad Sci USA. 2018;115(7):E1520–E1529. doi:10.1073/pnas.1710401115.
  • Xiao Y, Lai L, Chen H, et al. Interleukin-33 deficiency exacerbated experimental autoimmune encephalomyelitis with an influence on immune cells and glia cells. Mol Immunol. 2018;101:550–563. doi:10.1016/j.molimm.2018.08.026.
  • Finlay CM, Cunningham KT, Doyle B, Mills KHG. IL-33-stimulated murine mast cells polarize alternatively activated macrophages, which suppress T cells that mediate experimental autoimmune encephalomyelitis. J Immunol. 2020;205(7):1909–1919. doi:10.4049/jimmunol.1901321.
  • Dhaeze T, Lachance C, Tremblay L, et al. Sex-dependent factors encoded in the immune compartment dictate relapsing or progressive phenotype in demyelinating disease. JCI Insight. 2019;4(6). doi:10.1172/jci.insight.124885.
  • Bouhassira D. Neuropathic pain: definition, assessment and epidemiology. Rev Neurol (Paris)). 2019;175(1-2):16–25. doi:10.1016/j.neurol.2018.09.016.
  • Sorge RE, Mapplebeck JCS, Rosen S, et al. Different immune cells mediate mechanical pain hypersensitivity in male and female mice. Nat Neurosci. 2015;18(8):1081–1083. doi:10.1038/nn.4053.
  • Chernov AV, Hullugundi SK, Eddinger KA, et al. A myelin basic protein fragment induces sexually dimorphic transcriptome signatures of neuropathic pain in mice. J Biol Chem. 2020;295(31):10807–10821. doi:10.1074/jbc.RA120.013696.
  • Kobayashi Y, Kiguchi N, Fukazawa Y, et al. Macrophage-T cell interactions mediate neuropathic pain through the glucocorticoid-induced tumor necrosis factor ligand system. J Biol Chem. 2015;290(20):12603–12613. doi:10.1074/jbc.M115.636506.
  • Cao L, DeLeo JA. CNS-infiltrating CD4+ T lymphocytes contribute to murine spinal nerve transection-induced neuropathic pain. Eur J Immunol. 2008;38(2):448–458. doi:10.1002/eji.200737485.
  • Costigan M, Moss A, Latremoliere A, et al. T-cell infiltration and signaling in the adult dorsal spinal cord is a major contributor to neuropathic pain-like hypersensitivity. J Neurosci. 2009;29(46):14415–14422. doi:10.1523/JNEUROSCI.4569-09.2009.
  • Moalem G, Xu K, Yu L. T lymphocytes play a role in neuropathic pain following peripheral nerve injury in rats. Neuroscience. 2004;129(3):767–777. doi:10.1016/j.neuroscience.2004.08.035.
  • Cobos EJ, Nickerson CA, Gao F, et al. Mechanistic differences in neuropathic pain modalities revealed by correlating behavior with global expression profiling. Cell Rep. 2018;22(5):1301–1312. doi:10.1016/j.celrep.2018.01.006.
  • Kleinschnitz C, Hofstetter HH, Meuth SG, et al. T cell infiltration after chronic constriction injury of mouse sciatic nerve is associated with interleukin-17 expression. Exp Neurol. 2006;200(2):480–485. doi:10.1016/j.expneurol.2006.03.014.
  • Kim CF, Moalem-Taylor G. Interleukin-17 contributes to neuroinflammation and neuropathic pain following peripheral nerve injury in mice. J Pain. 2011;12(3):370–383. doi:10.1016/j.jpain.2010.08.003.
  • Schmid AB, Coppieters MW, Ruitenberg MJ, McLachlan EM. Local and remote immune-mediated inflammation after mild peripheral nerve compression in rats. J Neuropathol Exp Neurol. 2013;72(7):662–680. doi:10.1097/NEN.0b013e318298de5b.
  • Davoli-Ferreira M, de Lima KA, Fonseca MM, et al. Regulatory T cells counteract neuropathic pain through inhibition of the Th1 response at the site of peripheral nerve injury. PainPublish Ahead of Print. 2020;161(8):1730–1743. doi:10.1097/j.pain.0000000000001879.
  • Noor S, et al. LFA-1 antagonist (BIRT377) similarly reverses peripheral neuropathic pain in male and female mice with underlying sex divergent peripheral immune proinflammatory phenotypes. Neuroimmunol Neuroinflammation. 2019;6.
  • Day Y-J, Liou J-T, Lee C-M, et al. Lack of interleukin-17 leads to a modulated micro-environment and amelioration of mechanical hypersensitivity after peripheral nerve injury in mice. Pain. 2014;155(7):1293–1302. doi:10.1016/j.pain.2014.04.004.
  • Hartlehnert M, Derksen A, Hagenacker T, et al. Schwann cells promote post-traumatic nerve inflammation and neuropathic pain through MHC class II. Sci Rep. 2017;7(1):12518. doi:10.1038/s41598-017-12744-2.
  • Hu P, Bembrick AL, Keay KA, McLachlan EM. Immune cell involvement in dorsal root ganglia and spinal cord after chronic constriction or transection of the rat sciatic nerve. Brain Behav Immun. 2007;21(5):599–616. doi:10.1016/j.bbi.2006.10.013.
  • Hu P, McLachlan EM. Macrophage and lymphocyte invasion of dorsal root ganglia after peripheral nerve lesions in the rat. Neuroscience. 2002;112(1):23–38. doi:10.1016/S0306-4522(02)00065-9.
  • Du B, Ding Y-Q, Xiao X, et al. CD4+ αβ T cell infiltration into the leptomeninges of lumbar dorsal roots contributes to the transition from acute to chronic mechanical allodynia after adult rat tibial nerve injuries. J Neuroinflammation. 2018;15(1):81. doi:10.1186/s12974-018-1115-7.
  • Donnelly CR, Andriessen AS, Chen G, et al. Central nervous system targets: glial cell mechanisms in chronic pain. Neurotherapeutics. 2020;17(3):846–860. doi:10.1007/s13311-020-00905-7.
  • Sun C, Zhang J, Chen L, et al. IL-17 contributed to the neuropathic pain following peripheral nerve injury by promoting astrocyte proliferation and secretion of proinflammatory cytokines. Mol Med Rep. 2017;15(1):89–96. doi:10.3892/mmr.2016.6018.
  • Tsuda M, Masuda T, Kitano J, et al. IFN-gamma receptor signaling mediates spinal microglia activation driving neuropathic pain. Proc Natl Acad Sci USA. 2009;106(19):8032–8037. doi:10.1073/pnas.0810420106.
  • Draleau K, et al. Phenotypic identification of spinal cord-infiltrating CD4+ T lymphocytes in a murine model of neuropathic pain. J. Pain Relief. 2014;Suppl 3(003).
  • Kavelaars A, C. J H. T-cells as guardians of pain resolution. Trends Mol Med. 2021;
  • Labuz D, Schreiter A, Schmidt Y, Brack A, Machelska H. T lymphocytes containing β-endorphin ameliorate mechanical hypersensitivity following nerve injury. Brain Behav Immun. 2010;24(7):1045–1053. doi:10.1016/j.bbi.2010.04.001.
  • Plein LM, Rittner HL. Opioids and the immune system - friend or foe. Br J Pharmacol. 2018;175(14):2717–2725. doi:10.1111/bph.13750.
  • Lees JG, Duffy SS, Perera CJ, Moalem-Taylor G. Depletion of Foxp3+ regulatory T cells increases severity of mechanical allodynia and significantly alters systemic cytokine levels following peripheral nerve injury. Cytokine. 2015;71(2):207–214. doi:10.1016/j.cyto.2014.10.028.
  • Fischer R, Sendetski M, Del Rivero T, et al. TNFR2 promotes Treg-mediated recovery from neuropathic pain across sexes. Proc Natl Acad Sci USA. 2019;116(34):17045–17050. doi:10.1073/pnas.1902091116.
  • Kwilasz AJ, Grace PM, Serbedzija P, Maier SF, Watkins LR. The therapeutic potential of interleukin-10 in neuroimmune diseases. Neuropharmacology. 2015;96(Pt A):55–69. doi:10.1016/j.neuropharm.2014.10.020.
  • Amariuta T, Luo Y, Knevel R, Okada Y, Raychaudhuri S. Advances in genetics toward identifying pathogenic cell states of rheumatoid arthritis. Immunol Rev. 2020;294(1):188–204. doi:10.1111/imr.12827.
  • Vyas SP, Hansda AK, Goswami R. Rheumatoid arthritis: ‘melting pot’ of T helper subsets. Int Rev Immunol. 2019;38(5):212–231. doi:10.1080/08830185.2019.1621865.
  • Bauer ME. Accelerated immunosenescence in rheumatoid arthritis: impact on clinical progression. Immun Ageing. 2020;17:6. doi:10.1186/s12979-020-00178-w.
  • van Vollenhoven RF. Sex differences in rheumatoid arthritis: more than meets the eye. BMC Med. 2009;7:12. doi:10.1186/1741-7015-7-12.
  • Albrecht K. [Gender-specific differences in comorbidities of rheumatoid arthritis]. Z Rheumatol. 2014;73(7):607–614. doi:10.1007/s00393-014-1410-3.
  • Goemaere S, Ackerman C, Goethals K, et al. Onset of symptoms of rheumatoid arthritis in relation to age, sex and menopausal transition. J Rheumatol. 1990;17(12):1620–1622.
  • Maynard C, Mikuls TR, Cannon GW, et al. Sex differences in the achievement of remission and low disease activity in rheumatoid arthritis. Arthritis Care Res. 2020;72(3):326–333. doi:10.1002/acr.23873.
  • Wallenius M, Skomsvoll JF, Koldingsnes W, et al. Comparison of work disability and health-related quality of life between males and females with rheumatoid arthritis below the age of 45 years. Scand. J. Rheumatol. 2009;38(3):178–183. doi:10.1080/03009740802400594.
  • Favalli EG, Biggioggero M, Crotti C, et al. Sex and management of rheumatoid arthritis. Clin Rev Allergy Immunol. 2019;56(3):333–345. doi:10.1007/s12016-018-8672-5.
  • Weyand CM, Goronzy JJ. The immunology of rheumatoid arthritis. Nat Immunol. 2021;22(1):10–18. doi:10.1038/s41590-020-00816-x.
  • van der Woude D, van der Helm-van Mil AHM. Update on the epidemiology, risk factors, and disease outcomes of rheumatoid arthritis. Best Pract Res Clin Rheumatol. 2018;32(2):174–187. doi:10.1016/j.berh.2018.10.005.
  • Gameiro J, Nagib P, Verinaud L. The thymus microenvironment in regulating thymocyte differentiation. Cell Adhes. Migr. 2010;4(3):382–390. doi:10.4161/cam.4.3.11789.
  • Giannini D, Antonucci M, Petrelli F, et al. One year in review 2020: pathogenesis of rheumatoid arthritis. Clin Exp Rheumatol. 2020;38(3):387–397.
  • Wehr P, Purvis H, Law S-C, Thomas R. Dendritic cells, T cells and their interaction in rheumatoid arthritis. Clin Exp Immunol. 2019;196(1):12–27. doi:10.1111/cei.13256.
  • Auréal M, Machuca-Gayet I, Coury F. Rheumatoid Arthritis in the View of Osteoimmunology. Biomolecules. 2020;11(1):48. doi:10.3390/biom11010048.
  • van Onna M, Boonen A. The challenging interplay between rheumatoid arthritis, ageing and comorbidities. BMC Musculoskelet Disord. 2016;17:184. doi:10.1186/s12891-016-1038-3.
  • Taylor PC, et al. The key comorbidities in patients with rheumatoid arthritis: a narrative review. J Clin Med. 2021;10.
  • Basile MS, et al. Cognitive decline in rheumatoid arthritis: insight into the molecular pathogenetic mechanisms. Int J Mol Sci. 2021;22.
  • Bartok B, Firestein GS. Fibroblast-like synoviocytes: key effector cells in rheumatoid arthritis. Immunol Rev. 2010;233(1):233–255. doi:10.1111/j.0105-2896.2009.00859.x.
  • Cai W-W, Yu Y, Zong S-Y, Wei F. Metabolic reprogramming as a key regulator in the pathogenesis of rheumatoid arthritis. Inflamm Res. 2020;69(11):1087–1101. doi:10.1007/s00011-020-01391-5.
  • Li Y, Goronzy JJ, Weyand CM. DNA damage, metabolism and aging in pro-inflammatory T cells: rheumatoid arthritis as a model system. Exp Gerontol. 2018;105:118–127. doi:10.1016/j.exger.2017.10.027.
  • Hu X, Wu Y-J, Zhang J, Wei W. T-cells interact with B cells, dendritic cells, and fibroblast-like synoviocytes as hub-like key cells in rheumatoid arthritis. Int Immunopharmacol. 2019;70:428–434. doi:10.1016/j.intimp.2019.03.008.
  • Schneider A, Rieck M, Sanda S, et al. The effector T cells of diabetic subjects are resistant to regulation via CD4+ FOXP3+ regulatory T cells. J Immunol. 2008;181(10):7350–7355. doi:10.4049/jimmunol.181.10.7350.
  • Weyand CM, Wu B, Goronzy JJ. The metabolic signature of T cells in rheumatoid arthritis. Curr Opin Rheumatol. 2020;32(2):159–167. doi:10.1097/BOR.0000000000000683.
  • Chemin K, Gerstner C, Malmström V. Effector functions of CD4+ T cells at the site of local autoimmune inflammation-lessons from rheumatoid arthritis. Front Immunol. 2019;10:353. doi:10.3389/fimmu.2019.00353.
  • Kamali AN, Noorbakhsh SM, Hamedifar H, et al. A role for Th1-like Th17 cells in the pathogenesis of inflammatory and autoimmune disorders. Mol Immunol. 2019;105:107–115. doi:10.1016/j.molimm.2018.11.015.
  • Bank I. The role of gamma delta T cells in autoimmune rheumatic diseases. Cells. 2020;9(2):462. doi:10.3390/cells9020462.
  • Jung JH, et al. Synovial fluid CD69 + CD8+ T cells with tissue-resident phenotype mediate perforin-dependent citrullination in rheumatoid arthritis. Clin Transl Immunol. 2020;9:e1140.
  • Li Y, Luo W, Zhu S, Lei G. T cells in osteoarthritis: alterations and beyond. Front Immunol. 2017;8 doi:10.3389/fimmu.2017.00356.
  • Woodell-May JE, Sommerfeld SD. Role of Inflammation and the immune system in the progression of osteoarthritis. J Orthop Res. 2020;38(2):253–257. doi:10.1002/jor.24457.
  • Cross M, Smith E, Hoy D, et al. The global burden of hip and knee osteoarthritis: estimates from the Global Burden of Disease 2010 study. Ann Rheum Dis. 2014;73(7):1323–1330. doi:10.1136/annrheumdis-2013-204763.
  • Haseeb A, Haqqi TM. Immunopathogenesis of osteoarthritis. Clin Immunol. 2013;146(3):185–196. doi:10.1016/j.clim.2012.12.011.
  • Kulkarni P, Martson A, Vidya R, Chitnavis S, Harsulkar A. Chapter Two - Pathophysiological landscape of osteoarthritis. In Makowski GS, Advances in Clinical Chemistry, Elsevier, 2021;100:37–90.
  • Kalaitzoglou E, Griffin TM, Humphrey MB. Innate immune responses and osteoarthritis. Curr Rheumatol Rep. 2017;19:45.
  • Livshits G, Kalinkovich A. Hierarchical, imbalanced pro-inflammatory cytokine networks govern the pathogenesis of chronic arthropathies. Osteoarthritis Cartilage. 2018;26(1):7–17. doi:10.1016/j.joca.2017.10.013.
  • Silawal S, Triebel J, Bertsch T, Schulze-Tanzil G. Osteoarthritis and the complement cascade. Clin Med Insights Arthritis Musculoskelet Disord. 2018;11:11795441177514301179544117751430 doi:10.1177/1179544117751430.
  • Chow YY, Chin K-Y. The role of inflammation in the pathogenesis of osteoarthritis. Mediators Inflamm. 2020;2020:1–19. doi:10.1155/2020/8293921.
  • Mehana E-SE, Khafaga AF, El-Blehi SS. The role of matrix metalloproteinases in osteoarthritis pathogenesis: An updated review. Life Sci. 2019;234:116786. doi:10.1016/j.lfs.2019.116786.
  • Lopes EBP, Filiberti A, Husain SA, Humphrey MB. Immune contributions to osteoarthritis. Curr Osteoporos Rep. 2017;15(6):593–600. doi:10.1007/s11914-017-0411-y.
  • Ishii H, Tanaka H, Katoh K, et al. Characterization of infiltrating T cells and Th1/Th2-type cytokines in the synovium of patients with osteoarthritis. Osteoarthritis Cartilage. 2002;10(4):277–281. doi:10.1053/joca.2001.0509.
  • Zhu W, Zhang X, Jiang Y, et al. Alterations in peripheral T cell and B cell subsets in patients with osteoarthritis. Clin Rheumatol. 2020;39(2):523–532. doi:10.1007/s10067-019-04768-y.
  • Nees TA, et al. T helper cell infiltration in osteoarthritis-related knee pain and disability. J Clin Med. 2020;9.
  • Rosshirt N, Hagmann S, Tripel E, et al. A predominant Th1 polarization is present in synovial fluid of end-stage osteoarthritic knee joints: analysis of peripheral blood, synovial fluid and synovial membrane. Clin Exp Immunol. 2019;195(3):395–406. doi:10.1111/cei.13230.
  • Sakkas LI, Platsoucas CD. The role of T cells in the pathogenesis of osteoarthritis. Arthritis Rheum. 2007;56(2):409–424. doi:10.1002/art.22369.
  • Sakata M, et al. Osteoarthritic articular chondrocytes stimulate autologous T cell responses in vitro. Clin Exp Rheumatol. 2003;21:704–710.
  • Platzer H, et al. Impact of mononuclear cell infiltration on chondrodestructive MMP/ADAMTS production in osteoarthritic knee joints-an ex vivo study. J Clin Med. 2020;9.
  • Sussman M, Benner J, Haller MJ, Rewers M, Griffiths R. Estimated lifetime economic burden of type 1 diabetes. Diabetes Technol Ther. 2020;22(2):121–130. doi:10.1089/dia.2019.0398.
  • Chiang JL, Kirkman MS, Laffel LMB, Peters AL. Type 1 diabetes through the life span: a position statement of the American Diabetes Association. Diabetes Care. 2014;37(7):2034–2054. doi:10.2337/dc14-1140.
  • Ilonen J, Lempainen J, Veijola R. The heterogeneous pathogenesis of type 1 diabetes mellitus. Nat Rev Endocrinol. 2019;15(11):635–650. doi:10.1038/s41574-019-0254-y.
  • Singh B, Delovitch TL. Immune mechanisms that regulate susceptibility to autoimmune type I diabetes. CRIAI. 2000;19(3):247–264. doi:10.1385/CRIAI:19:3:247.
  • Han S, Donelan W, Wang H, Reeves W, Yang L-J. Novel autoantigens in type 1 diabetes. Am J Transl Res. 2013;5(4):379–392.
  • Jacobson DL, Gange SJ, Rose NR, Graham NM. Epidemiology and estimated population burden of selected autoimmune diseases in the United States. Clin Immunol Immunopathol. 1997;84(3):223–243. doi:10.1006/clin.1997.4412.
  • Frommer L, Kahaly GJ. Type 1 diabetes and associated autoimmune diseases. World J Diabetes. 2020;11(11):527–539. doi:10.4239/wjd.v11.i11.527.
  • Young EF, Hess PR, Arnold LW, Tisch R, Frelinger JA. Islet lymphocyte subsets in male and female NOD mice are qualitatively similar but quantitatively distinct. Autoimmunity. 2009;42(8):678–691. doi:10.3109/08916930903213993.
  • Campbell-Thompson M, Fu A, Kaddis JS, et al. Insulitis and β-cell mass in the natural history of type 1 diabetes. Diabetes. 2016;65(3):719–731. doi:10.2337/db15-0779.
  • Campbell-Thompson ML, Atkinson MA, Butler AE, et al. The diagnosis of insulitis in human type 1 diabetes. Diabetologia. 2013;56(11):2541–2543. doi:10.1007/s00125-013-3043-5.
  • Kay TW, Parker JL, Stephens LA, Thomas HE, Allison J. RIP-beta 2-microglobulin transgene expression restores insulitis, but not diabetes, in beta 2-microglobulin null nonobese diabetic mice. J Immunol. 1996;157(8):3688–3693.
  • Foulis AK, Farquharson MA, Hardman R. Aberrant expression of class II major histocompatibility complex molecules by B cells and hyperexpression of Class I major histocompatibility complex molecules by insulin containing islets in Type 1 (insulin-dependent) diabetes mellitus. Diabetologia. 1987;30(5):333–343. doi:10.1007/BF00299027.
  • Foulis AK, McGill M, Farquharson MA. Insulitis in type 1 (insulin-dependent) diabetes mellitus in man-macrophages, lymphocytes, and interferon-gamma containing cells. J Pathol. 1991;165(2):97–103. doi:10.1002/path.1711650203.
  • Willcox A, Richardson SJ, Bone AJ, Foulis AK, Morgan NG. Analysis of islet inflammation in human type 1 diabetes. Clin Exp Immunol. 2009;155(2):173–181. doi:10.1111/j.1365-2249.2008.03860.x.
  • Hamilton-Williams EE, Palmer SE, Charlton B, Slattery RM. Beta cell MHC class I is a late requirement for diabetes. Proc Natl Acad Sci USA. 2003;100(11):6688–6693. doi:10.1073/pnas.1131954100.
  • Falcone M, Fousteri G. Role of the PD-1/PD-L1 dyad in the maintenance of pancreatic immune tolerance for prevention of type 1 diabetes. Front Endocrinol. 2020;11 doi:10.3389/fendo.2020.00569.
  • Höglund P, Mintern J, Waltzinger C, et al. Initiation of autoimmune diabetes by developmentally regulated presentation of islet cell antigens in the pancreatic lymph nodes. J Exp Med. 1999;189(2):331–339. doi:10.1084/jem.189.2.331.
  • Hultgren B, Huang X, Dybdal N, Stewart TA. Genetic absence of -interferon delays but does not prevent diabetes in NOD mice. Diabetes. 1996;45(6):812–817. doi:10.2337/diabetes.45.6.812.
  • Kägi D, Odermatt B, Seiler P, et al. Reduced incidence and delayed onset of diabetes in perforin-deficient nonobese diabetic mice. J Exp Med. 1997;186(7):989–997. doi:10.1084/jem.186.7.989.
  • Savinov AY, Tcherepanov A, Green EA, Flavell RA, Chervonsky AV. Contribution of Fas to diabetes development. Proc Natl Acad Sci U S A. 2003;100(2):628–632. doi:10.1073/pnas.0237359100.
  • Wiedeman AE, Muir VS, Rosasco MG, et al. Autoreactive CD8+ T cell exhaustion distinguishes subjects with slow type 1 diabetes progression. J Clin Invest. 2020;130(1):480–490. doi:10.1172/JCI126595.
  • Arif S, Moore F, Marks K, et al. Peripheral and islet interleukin-17 pathway activation characterizes human autoimmune diabetes and promotes cytokine-mediated β-cell death. Diabetes. 2011;60(8):2112–2119. doi:10.2337/db10-1643.
  • Kuriya G, Uchida T, Akazawa S, et al. Double deficiency in IL-17 and IFN-γ signalling significantly suppresses the development of diabetes in the NOD mouse. Diabetologia. 2013;56(8):1773–1780. doi:10.1007/s00125-013-2935-8.
  • Campbell IL, Kay TW, Oxbrow L, Harrison LC. Essential role for interferon-gamma and interleukin-6 in autoimmune insulin-dependent diabetes in NOD/Wehi mice. J Clin Invest. 1991;87(2):739–742. doi:10.1172/JCI115055.
  • Debray-Sachs M, Carnaud C, Boitard C, et al. Prevention of diabetes in NOD mice treated with antibody to murine IFNγ. J. Autoimmun. 1991;4(2):237–248. doi:10.1016/0896-8411(91)90021-4.
  • von Herrath MG, Oldstone MB. Interferon-gamma is essential for destruction of beta cells and development of insulin-dependent diabetes mellitus. J Exp Med. 1997;185(3):531–539. doi:10.1084/jem.185.3.531.
  • Sobel DO, Han J, Williams J, et al. Gamma interferon paradoxically inhibits the development of diabetes in the NOD mouse. J Autoimmun. 2002;19(3):129–137. doi:10.1006/jaut.2002.0604.
  • Shapiro MR, Yeh W-I, Longfield JR, et al. CD226 deletion reduces type 1 diabetes in the NOD mouse by impairing thymocyte development and peripheral T cell activation. Front Immunol. 2020;11:2180. doi:10.3389/fimmu.2020.02180.
  • Eichmann M, Baptista R, Ellis RJ, et al. Costimulation blockade disrupts CD4+ T Cell memory pathways and uncouples their link to decline in β-Cell function in type 1 diabetes. J Immunol. 2020;204(12):3129–3138. doi:10.4049/jimmunol.1901439.
  • Terrazzano G, Bruzzaniti S, Rubino V, et al. T1D progression is associated with loss of CD3 + CD56+ regulatory T cells that control CD8+ T cell effector functions. Nat Metab. 2020;2(2):142–152. doi:10.1038/s42255-020-0173-1.
  • Brusko TM, Wasserfall CH, Clare-Salzler MJ, Schatz DA, Atkinson MA. Functional Defects and the Influence of Age on the Frequency of CD4+ CD25+ T-cells in type 1 diabetes. Diabetes. 2005;54(5):1407–1414. doi:10.2337/diabetes.54.5.1407.
  • Lindley S, Dayan CM, Bishop A, et al. Defective suppressor function in CD4(+)CD25(+) T-cells from patients with type 1 diabetes. Diabetes. 2005;54(1):92–99. doi:10.2337/diabetes.54.1.92.
  • Wen X, Yang J, James E, et al. Increased islet antigen-specific regulatory and effector CD4+ T cells in healthy individuals with the type 1 diabetes-protective haplotype. Sci Immunol. 2020;5(44):eaax8767. doi:10.1126/sciimmunol.aax8767.
  • Ryba M, Hak L, Zorena K, Myśliwiec M, Myśliwska J. [Regulatory T lymphocytes expressing L-selectin in children and adolescents with type 1 diabetes mellitus. Pediatr Endocrinol Diabetes Metab. 2010;16(1):12–16.
  • Wildin RS, Ramsdell F, Peake J, et al. X-linked neonatal diabetes mellitus, enteropathy and endocrinopathy syndrome is the human equivalent of mouse scurfy. Nat Genet. 2001;27(1):18–20. doi:10.1038/83707.
  • Serr I, Scherm MG, Zahm AM, et al. A miRNA181a/NFAT5 axis links impaired T cell tolerance induction with autoimmune type 1 diabetes. Sci Transl Med. 2018;10(422):eaag1782. doi:10.1126/scitranslmed.aag1782.
  • Zhang J, Chen L, Wang F, et al. Extracellular HMGB1 exacerbates autoimmune progression and recurrence of type 1 diabetes by impairing regulatory T cell stability. Diabetologia. 2020;63(5):987–1001. doi:10.1007/s00125-020-05105-8.

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.