271
Views
0
CrossRef citations to date
0
Altmetric
Review Articles

STATs signaling pathways in dendritic cells: As potential therapeutic targets?

, , , , , , , , , , & show all
Pages 138-159 | Received 25 Jul 2023, Accepted 16 Oct 2023, Published online: 27 Oct 2023

References

  • Mildner A, Jung S. Development and function of dendritic cell subsets. Immunity. 2014;40(5):642–656. doi:10.1016/j.immuni.2014.04.016.
  • van Nierop K, de Groot C. Human follicular dendritic cells: function, origin and development. Semin Immunol. 2002;14:251. doi:10.1016/s1044-5323(02)00057-x.
  • El-Awady AR, Elashiry M, Morandini AC, Meghil MM, Cutler CW. Dendritic cells a critical link to alveolar bone loss and systemic disease risk in periodontitis: immunotherapeutic implications. Periodontol 2000. 2022;89(1):41–50. doi:10.1111/prd.12428.
  • Iberg CA, Jones A, Hawiger D. Dendritic cells as inducers of peripheral tolerance. Trends Immunol. 2017;38(11):793–804. doi:10.1016/j.it.2017.07.007.
  • Dudek AM, Martin S, Garg AD, Agostinis P. Immature, semi-mature, and fully mature dendritic cells: toward a DC-cancer cells interface that augments anticancer immunity. Front Immunol. 2013;4:438. doi:10.3389/fimmu.2013.00438.
  • Li HS, Watowich SS. Diversification of dendritic cell subsets: emerging roles for STAT proteins. JAKSTAT. 2013;2(4):e25112. doi:10.4161/jkst.25112.
  • Kool M, van Loo G, Waelput W, et al. The ubiquitin-editing protein A20 prevents dendritic cell activation, recognition of apoptotic cells, and systemic autoimmunity. Immunity. 2011;35(1):82–96. doi:10.1016/j.immuni.2011.05.013.
  • de Noronha S, Hardy S, Sinclair J, et al. Impaired dendritic-cell homing in vivo in the absence of Wiskott-Aldrich syndrome protein. Blood. 2005;105(4):1590–1597. doi:10.1182/blood-2004-06-2332.
  • Fu X-Y, Schindler C, Improta T, Aebersold R, Darnell Jr JE. The proteins of ISGF-3, the interferon alpha-induced transcriptional activator, define a gene family involved in signal transduction. Proc Natl Acad Sci U S A. 1992;89(16):7840–7843. doi:10.1073/pnas.89.16.7840.
  • Sehgal P, Levy DE, Hirano T. Signal Transducers and Activators of Transcription (STATs): Activation and Biology. Springer Science & Business Media; 2013.
  • Owen KL, Brockwell NK, Parker BS. JAK-STAT signaling: a double-edged sword of immune regulation and cancer progression. Cancers (Basel). 2019;11(12):2002. doi:10.3390/cancers11122002.
  • Pellegrini S, Dusanter-Fourt I. The structure, regulation and function of the Janus kinases (JAKs) and the signal transducers and activators of transcription (STATs). Eur J Biochem. 1997;248(3):615–633. doi:10.1111/j.1432-1033.1997.00615.x.
  • Guanizo AC, Fernando CD, Garama DJ, Gough DJ. STAT3: a multifaceted oncoprotein. Growth Factors. 2018;36(1–2):1–14. doi:10.1080/08977194.2018.1473393.
  • Bromberg JF. Activation of STAT proteins and growth control. Bioessays. 2001;23(2):161–169. doi:10.1002/1521-1878(200102)23:2<161::AID-BIES1023>3.0.CO;2-0.
  • Akira S. Functional roles of STAT family proteins: lessons from knockout mice. Stem Cells. 1999;17(3):138–146. doi:10.1002/stem.170138.
  • Collin M, Bigley V. Human dendritic cell subsets: an update. Immunology. 2018;154(1):3–20. doi:10.1111/imm.12888.
  • Domínguez PM, Ardavín C. Differentiation and function of mouse monocyte-derived dendritic cells in steady state and inflammation. Immunol Rev. 2010;234(1):90–104. doi:10.1111/j.0105-2896.2009.00876.x.
  • Gardner A, Ruffell B. Dendritic cells and cancer immunity. Trends Immunol. 2016;37(12):855–865. doi:10.1016/j.it.2016.09.006.
  • Colbert JD, Cruz FM, Rock KL. Cross-presentation of exogenous antigens on MHC I molecules. Curr Opin Immunol. 2020;64:1–8. doi:10.1016/j.coi.2019.12.005.
  • Wculek SK, Cueto FJ, Mujal AM, Melero I, Krummel MF, Sancho D. Dendritic cells in cancer immunology and immunotherapy. Nat Rev Immunol. 2020;20(1):7–24. doi:10.1038/s41577-019-0210-z.
  • Patente TA, Pinho MP, Oliveira AA, Evangelista GCM, Bergami-Santos PC, Barbuto JAM. Human dendritic cells: their heterogeneity and clinical application potential in cancer immunotherapy. Front Immunol. 2018;9:3176. doi:10.3389/fimmu.2018.03176.
  • Gerhard GM, Bill R, Messemaker M, Klein AM, Pittet MJ. Tumor-infiltrating dendritic cell states are conserved across solid human cancers. J Exp Med. 2021;218(1):e20200264. doi:10.1084/jem.20200264.
  • Steinman RM. Decisions about dendritic cells: past, present, and future. Annu Rev Immunol. 2012;30(1):1–22. doi:10.1146/annurev-immunol-100311-102839.
  • Merad M, Sathe P, Helft J, Miller J, Mortha A. The dendritic cell lineage: ontogeny and function of dendritic cells and their subsets in the steady state and the inflamed setting. Annu Rev Immunol. 2013;31(1):563–604. doi:10.1146/annurev-immunol-020711-074950.
  • McKenna HJ, Stocking KL, Miller RE, et al. Mice lacking flt3 ligand have deficient hematopoiesis affecting hematopoietic progenitor cells, dendritic cells, and natural killer cells. Blood. 2000;95(11):3489–3497.
  • O'Keeffe M, Mok WH, Radford KJ. Human dendritic cell subsets and function in health and disease. Cell Mol Life Sci. 2015;72(22):4309–4325. doi:10.1007/s00018-015-2005-0.
  • Haniffa M, Shin A, Bigley V, et al. Human tissues contain CD141hi cross-presenting dendritic cells with functional homology to mouse CD103+ nonlymphoid dendritic cells. Immunity. 2012;37(1):60–73. doi:10.1016/j.immuni.2012.04.012.
  • Schulz O, Diebold SS, Chen M, et al. Toll-like receptor 3 promotes cross-priming to virus-infected cells. Nature. 2005;433(7028):887–892. doi:10.1038/nature03326.
  • Fuertes Marraco SA, Grosjean F, Duval A, et al. Novel murine dendritic cell lines: a powerful auxiliary tool for dendritic cell research. Front Immunol. 2012;3:331. doi:10.3389/fimmu.2012.00331.
  • Smita S, Ahad A, Ghosh A, et al. Importance of EMT factor ZEB1 in cDC1 "MutuDC Line" mediated induction of Th1 immune response. Front Immunol. 2018;9:2604. doi:10.3389/fimmu.2018.02604.
  • Mashayekhi M, Sandau MM, Dunay IR, et al. CD8α(+) dendritic cells are the critical source of interleukin-12 that controls acute infection by Toxoplasma gondii tachyzoites. Immunity. 2011;35(2):249–259. doi:10.1016/j.immuni.2011.08.008.
  • Grajales-Reyes GE, Iwata A, Albring J, et al. Batf3 maintains autoactivation of Irf8 for commitment of a CD8α(+) conventional DC clonogenic progenitor. Nat Immunol. 2015;16(7):708–717. doi:10.1038/ni.3197.
  • Kretzer NM, Theisen DJ, Tussiwand R, et al. RAB43 facilitates cross-presentation of cell-associated antigens by CD8α+ dendritic cells. J Exp Med. 2016;213(13):2871–2883. doi:10.1084/jem.20160597.
  • Martínez-López M, Iborra S, Conde-Garrosa R, Sancho D. Batf3-dependent CD103+ dendritic cells are major producers of IL-12 that drive local Th1 immunity against Leishmania major infection in mice. Eur J Immunol. 2015;45(1):119–129. doi:10.1002/eji.201444651.
  • Bachem A, Güttler S, Hartung E, et al. Superior antigen cross-presentation and XCR1 expression define human CD11c + CD141+ cells as homologues of mouse CD8+ dendritic cells. J Exp Med. 2010;207(6):1273–1281. doi:10.1084/jem.20100348.
  • Liu S, Cai X, Wu J, et al. Phosphorylation of innate immune adaptor proteins MAVS, STING, and TRIF induces IRF3 activation. Science. 2015;347(6227):aaa2630. doi:10.1126/science.aaa2630.
  • Molenkamp BG, van Leeuwen PA, Meijer S, et al. Intradermal CpG-B activates both plasmacytoid and myeloid dendritic cells in the sentinel lymph node of melanoma patients. Clin Cancer Res. 2007;13(10):2961–2969. doi:10.1158/1078-0432.CCR-07-0050.
  • Janela B, Patel AA, Lau MC, et al. A subset of type I conventional dendritic cells controls cutaneous bacterial infections through VEGFα-mediated recruitment of neutrophils. Immunity. 2019;50(4):1069–1083.e8. doi:10.1016/j.immuni.2019.03.001.
  • Del Fresno C, Saz-Leal P, Enamorado M, et al. DNGR-1 in dendritic cells limits tissue damage by dampening neutrophil recruitment. Science. 2018;362(6412):351–356. doi:10.1126/science.aan8423.
  • Heger L, Balk S, Lühr JJ, et al. CLEC10A is a specific marker for human CD1c(+) dendritic cells and enhances their toll-like receptor 7/8-induced cytokine secretion. Front Immunol. 2018;9:744. doi:10.3389/fimmu.2018.00744.
  • Villani AC, Satija R, Reynolds G, et al. Single-cell RNA-seq reveals new types of human blood dendritic cells, monocytes, and progenitors. Science. 2017;356(6335):eaah4573. doi:10.1126/science.aah4573.
  • Schlitzer A, McGovern N, Teo P, et al. IRF4 transcription factor-dependent CD11b + dendritic cells in human and mouse control mucosal IL-17 cytokine responses. Immunity. 2013;38(5):970–983. doi:10.1016/j.immuni.2013.04.011.
  • Hambleton S, Salem S, Bustamante J, et al. IRF8 mutations and human dendritic-cell immunodeficiency. N Engl J Med. 2011;365(2):127–138. doi:10.1056/NEJMoa1100066.
  • Matsuo K, Yoshie O, Kitahata K, Kamei M, Hara Y, Nakayama T. Recent progress in dendritic cell-based cancer immunotherapy. Cancers (Basel). 2021;13(10):2495. doi:10.3390/cancers13102495.
  • Tussiwand R, Everts B, Grajales-Reyes GE, et al. Klf4 expression in conventional dendritic cells is required for T helper 2 cell responses. Immunity. 2015;42(5):916–928. doi:10.1016/j.immuni.2015.04.017.
  • Persson EK, Uronen-Hansson H, Semmrich M, et al. IRF4 transcription-factor-dependent CD103(+)CD11b(+) dendritic cells drive mucosal T helper 17 cell differentiation. Immunity. 2013;38(5):958–969. doi:10.1016/j.immuni.2013.03.009.
  • Shin C, Han JA, Choi B, Cho YK, Do Y, Ryu S. Intrinsic features of the CD8α(-) dendritic cell subset in inducing functional T follicular helper cells. Immunol Lett. 2016;172:21–28. doi:10.1016/j.imlet.2016.01.009.
  • Nizzoli G, Larghi P, Paroni M, et al. IL-10 promotes homeostatic proliferation of human CD8(+) memory T cells and, when produced by CD1c(+) DCs, shapes naive CD8(+) T-cell priming. Eur J Immunol. 2016;46(7):1622–1632. doi:10.1002/eji.201546136.
  • Watchmaker PB, Lahl K, Lee M, et al. Comparative transcriptional and functional profiling defines conserved programs of intestinal DC differentiation in humans and mice. Nat Immunol. 2014;15(1):98–108. doi:10.1038/ni.2768.
  • Bamboat ZM, Stableford JA, Plitas G, et al. Human liver dendritic cells promote T cell hyporesponsiveness. J Immunol. 2009;182(4):1901–1911. doi:10.4049/jimmunol.0803404.
  • Reizis B, Bunin A, Ghosh HS, Lewis KL, Sisirak V. Plasmacytoid dendritic cells: recent progress and open questions. Annu Rev Immunol. 2011;29(1):163–183. doi:10.1146/annurev-immunol-031210-101345.
  • Cao W. Molecular characterization of human plasmacytoid dendritic cells. J Clin Immunol. 2009;29(3):257–264. doi:10.1007/s10875-009-9284-x.
  • Reizis B. Plasmacytoid dendritic cells: development, regulation, and function. Immunity. 2019;50(1):37–50. doi:10.1016/j.immuni.2018.12.027.
  • Villadangos JA, Young L. Antigen-presentation properties of plasmacytoid dendritic cells. Immunity. 2008;29(3):352–361. doi:10.1016/j.immuni.2008.09.002.
  • Dudziak D, Kamphorst AO, Heidkamp GF, et al. Differential antigen processing by dendritic cell subsets in vivo. Science. 2007;315(5808):107–111. doi:10.1126/science.1136080.
  • Caro AA, Deschoemaeker S, Allonsius L, Coosemans A, Laoui D. Dendritic cell vaccines: a promising approach in the fight against ovarian cancer. Cancers (Basel). 2022;14(16):4037. doi:10.3390/cancers14164037.
  • Persson CM, Chambers BJ. Plasmacytoid dendritic cell-induced migration and activation of NK cells in vivo. Eur J Immunol. 2010;40(8):2155–2164. doi:10.1002/eji.200940098.
  • Camisaschi C, De Filippo A, Beretta V, et al. Alternative activation of human plasmacytoid DCs in vitro and in melanoma lesions: involvement of LAG-3. J Invest Dermatol. 2014;134(7):1893–1902. doi:10.1038/jid.2014.29.
  • León B, López-Bravo M, Ardavín C. Monocyte-derived dendritic cells formed at the infection site control the induction of protective T helper 1 responses against Leishmania. Immunity. 2007;26(4):519–531. doi:10.1016/j.immuni.2007.01.017.
  • Randolph GJ, Inaba K, Robbiani DF, Steinman RM, Muller WA. Differentiation of phagocytic monocytes into lymph node dendritic cells in vivo. Immunity. 1999;11(6):753–761. doi:10.1016/s1074-7613(00)80149-1.
  • Richter L, Landsverk OJB, Atlasy N, et al. Transcriptional profiling reveals monocyte-related macrophages phenotypically resembling DC in human intestine. Mucosal Immunol. 2018;11(5):1512–1523. doi:10.1038/s41385-018-0060-1.
  • Inaba K, Inaba M, Romani N, et al. Generation of large numbers of dendritic cells from mouse bone marrow cultures supplemented with granulocyte/macrophage colony-stimulating factor. J Exp Med. 1992;176(6):1693–1702. doi:10.1084/jem.176.6.1693.
  • Serbina NV, Salazar-Mather TP, Biron CA, Kuziel WA, Pamer EG. TNF/iNOS-producing dendritic cells mediate innate immune defense against bacterial infection. Immunity. 2003;19(1):59–70. doi:10.1016/s1074-7613(03)00171-7.
  • Plantinga M, Guilliams M, Vanheerswynghels M, et al. Conventional and monocyte-derived CD11b(+) dendritic cells initiate and maintain T helper 2 cell-mediated immunity to house dust mite allergen. Immunity. 2013;38(2):322–335. doi:10.1016/j.immuni.2012.10.016.
  • Segura E, Touzot M, Bohineust A, et al. Human inflammatory dendritic cells induce Th17 cell differentiation. Immunity. 2013;38(2):336–348. doi:10.1016/j.immuni.2012.10.018.
  • Shin KS, Jeon I, Kim BS, et al. Monocyte-derived dendritic cells dictate the memory differentiation of CD8(+) T cells during acute infection. Front Immunol. 2019;10:1887. doi:10.3389/fimmu.2019.01887.
  • Helft J, Böttcher J, Chakravarty P, et al. GM-CSF mouse bone marrow cultures comprise a heterogeneous population of CD11c(+)MHCII(+) macrophages and dendritic cells. Immunity. 2015;42(6):1197–1211. doi:10.1016/j.immuni.2015.05.018.
  • Anguille S, Willemen Y, Lion E, Smits EL, Berneman ZN. Dendritic cell vaccination in acute myeloid leukemia. Cytotherapy. 2012;14(6):647–656. doi:10.3109/14653249.2012.693744.
  • Lee JJ, Kook H, Park MS, et al. Immunotherapy using autologous monocyte-derived dendritic cells pulsed with leukemic cell lysates for acute myeloid leukemia relapse after autologous peripheral blood stem cell transplantation. J Clin Apher. 2004;19(2):66–70. doi:10.1002/jca.10080.
  • Merad M, Ginhoux F, Collin M. Origin, homeostasis and function of Langerhans cells and other langerin-expressing dendritic cells. Nat Rev Immunol. 2008;8(12):935–947. doi:10.1038/nri2455.
  • Romani N, Clausen BE, Stoitzner P. Langerhans cells and more: langerin-expressing dendritic cell subsets in the skin. Immunol Rev. 2010;234(1):120–141. doi:10.1111/j.0105-2896.2009.00886.x.
  • De Monte A, Olivieri C-V, Vitale S, et al. CD1c-related DCs that express CD207/langerin, but are distinguishable from Langerhans cells, are consistently present in human tonsils. Front Immunol. 2016;7:197. doi:10.3389/fimmu.2016.00197.
  • Kashem SW, Haniffa M, Kaplan DH. Antigen-presenting cells in the skin. Annu Rev Immunol. 2017;35(1):469–499. doi:10.1146/annurev-immunol-051116-052215.
  • Strobl H, Bello-Fernandez C, Riedl E, et al. flt3 ligand in cooperation with transforming growth factor-beta1 potentiates in vitro development of Langerhans-type dendritic cells and allows single-cell dendritic cell cluster formation under serum-free conditions. Blood. 1997;90(4):1425–1434.
  • Merad M, Manz MG, Karsunky H, et al. Langerhans cells renew in the skin throughout life under steady-state conditions. Nat Immunol. 2002;3(12):1135–1141. doi:10.1038/ni852.
  • Romano E, Cotari JW, Barreira da Silva R, et al. Human Langerhans cells use an IL-15R-α/IL-15/pSTAT5-dependent mechanism to break T-cell tolerance against the self-differentiation tumor antigen WT1. Blood. 2012;119(22):5182–5190. doi:10.1182/blood-2011-09-382200.
  • Banchereau J, T.-S L, Zurawski S, et al. The differential production of cytokines by human Langerhans cells and dermal CD14(+) DCs controls CTL priming. Blood. 2012;119(24):5742–5749.
  • Abd El-Aleem SA, Saber EA, Aziz NM, El-Sherif H, Abdelraof AM, Djouhri L. Follicular dendritic cells. J Cell Physiol. 2022;237(4):2019–2033. doi:10.1002/jcp.30662.
  • Aguzzi A, Kranich J, Krautler NJ. Follicular dendritic cells: origin, phenotype, and function in health and disease. Trends Immunol. 2014;35(3):105–113. doi:10.1016/j.it.2013.11.001.
  • Facchetti F, Simbeni M, Lorenzi L. Follicular dendritic cell sarcoma. Pathologica. 2021;113(5):316–329. doi:10.32074/1591-951X-331.
  • Kranich J, Krautler NJ, Falsig J, et al. Engulfment of cerebral apoptotic bodies controls the course of prion disease in a mouse strain-dependent manner. J Exp Med. 2010;207(10):2271–2281. doi:10.1084/jem.20092401.
  • Hanayama R, Tanaka M, Miyasaka K, et al. Autoimmune disease and impaired uptake of apoptotic cells in MFG-E8-deficient mice. Science. 2004;304(5674):1147–1150. doi:10.1126/science.1094359.
  • Isenberg DA, Manson JJ, Ehrenstein MR, Rahman A. Fifty years of anti-ds DNA antibodies: are we approaching journey’s end? Rheumatology (Oxford). 2007;46(7):1052–1056. doi:10.1093/rheumatology/kem112.
  • Moysi E, Petrovas C, Koup RA. The role of follicular helper CD4 T cells in the development of HIV-1 specific broadly neutralizing antibody responses. Retrovirology. 2018;15(1):54. doi:10.1186/s12977-018-0437-y.
  • McCulloch L, Brown KL, Bradford BM, et al. Follicular dendritic cell-specific prion protein (PrP) expression alone is sufficient to sustain prion infection in the spleen. PLoS Pathog. 2011;7(12):e1002402. doi:10.1371/journal.ppat.1002402.
  • Mok SW, Proia RL, Brinkmann V, Mabbott NA. B cell-specific S1PR1 deficiency blocks prion dissemination between secondary lymphoid organs. J Immunol. 2012;188(10):5032–5040. doi:10.4049/jimmunol.1200349.
  • Yeh CH, Shih HC, Hong HM, et al. Protective effect of wogonin on proinflammatory cytokine generation via Jak1/3-STAT1/3 pathway in lipopolysaccharide stimulated BV2 microglial cells. Toxicol Ind Health. 2015;31(10):960–966. doi:10.1177/0748233713485886.
  • Darnell JE, Jr., Kerr IM, Stark GR. Jak-STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins. Science. 1994;264(5164):1415–1421. doi:10.1126/science.8197455.
  • Bhattacharjee A, Shukla M, Yakubenko VP, Mulya A, Kundu S, Cathcart MK. IL-4 and IL-13 employ discrete signaling pathways for target gene expression in alternatively activated monocytes/macrophages. Free Radic Biol Med. 2013;54:1–16. doi:10.1016/j.freeradbiomed.2012.10.553.
  • Scheel-Toellner D, Wang K, Henriquez NV, et al. Cytokine-mediated inhibition of apoptosis in non-transformed T cells and neutrophils can be dissociated from protein kinase B activation. Eur J Immunol. 2002;32(2):486–493. doi:10.1002/1521-4141(200202)32:2<486::AID-IMMU486>3.0.CO;2-U.
  • Fielding CA, McLoughlin RM, McLeod L, et al. IL-6 regulates neutrophil trafficking during acute inflammation via STAT3. J Immunol. 2008;181(3):2189–2195. doi:10.4049/jimmunol.181.3.2189.
  • Gotthardt D, Sexl V. STATs in NK-cells: the good, the bad, and the ugly. Front Immunol. 2016;7:694. doi:10.3389/fimmu.2016.00694.
  • Tu S, Bhagat G, Cui G, et al. Overexpression of interleukin-1beta induces gastric inflammation and cancer and mobilizes myeloid-derived suppressor cells in mice. Cancer Cell. 2008;14(5):408–419. doi:10.1016/j.ccr.2008.10.011.
  • Trikha P, Carson WE.3rd. Signaling pathways involved in MDSC regulation. Biochim Biophys Acta. 2014;1846(1):55–65. doi:10.1016/j.bbcan.2014.04.003.
  • Dagur PK, Sharma B, Kumar G, et al. Mycobacterial antigen(s) induce anergy by altering TCR- and TCR/CD28-induced signalling events: insights into T-cell unresponsiveness in leprosy. Mol Immunol. 2010;47(5):943–952. doi:10.1016/j.molimm.2009.11.009.
  • Mullen AC, High FA, Hutchins AS, et al. Role of T-bet in commitment of TH1 cells before IL-12-dependent selection. Science. 2001;292(5523):1907–1910. doi:10.1126/science.1059835.
  • O'Shea JJ, Plenge R. JAK and STAT signaling molecules in immunoregulation and immune-mediated disease. Immunity. 2012;36(4):542–550. doi:10.1016/j.immuni.2012.03.014.
  • Liao W, Schones DE, Oh J, et al. Priming for T helper type 2 differentiation by interleukin 2-mediated induction of interleukin 4 receptor alpha-chain expression. Nat Immunol. 2008;9(11):1288–1296. doi:10.1038/ni.1656.
  • Bell E. New player in the generation of TH17 cells. Nat Rev Immunol. 2007;7(8):581–581. doi:10.1038/nri2139.
  • Yu CR, Dambuza IM, Lee YJ, Frank GM, Egwuagu CE. STAT3 regulates proliferation and survival of CD8+ T cells: enhances effector responses to HSV-1 infection, and inhibits IL-10+ regulatory CD8+ T cells in autoimmune uveitis. Mediators Inflamm. 2013;2013:359674–359610. doi:10.1155/2013/359674.
  • Qin JZ, Zhang CL, Kamarashev J, Dummer R, Burg G, Döbbeling U. Interleukin-7 and interleukin-15 regulate the expression of the bcl-2 and c-myb genes in cutaneous T-cell lymphoma cells. Blood. 2001;98(9):2778–2783. doi:10.1182/blood.v98.9.2778.
  • Kim HP, Leonard WJ. CREB/ATF-dependent T cell receptor-induced FoxP3 gene expression: a role for DNA methylation. J Exp Med. 2007;204(7):1543–1551. doi:10.1084/jem.20070109.
  • Malin S, McManus S, Cobaleda C, et al. Role of STAT5 in controlling cell survival and immunoglobulin gene recombination during pro-B cell development. Nat Immunol. 2010;11(2):171–179. doi:10.1038/ni.1827.
  • Nemoto K, Kawanami T, Hoshina T, et al. Impaired B-cell differentiation in a patient With STAT1 gain-of-function mutation. Front Immunol. 2020;11:557521. doi:10.3389/fimmu.2020.557521.
  • Li HS, Gelbard A, Martinez GJ, et al. Cell-intrinsic role for IFN-α-STAT1 signals in regulating murine Peyer patch plasmacytoid dendritic cells and conditioning an inflammatory response. Blood. 2011;118(14):3879–3889. doi:10.1182/blood-2011-04-349761.
  • Jackson SH, Yu CR, Mahdi RM, Ebong S, Egwuagu CE. Dendritic cell maturation requires STAT1 and is under feedback regulation by suppressors of cytokine signaling. J Immunol. 2004;172(4):2307–2315. doi:10.4049/jimmunol.172.4.2307.
  • Le Bon A, Etchart N, Rossmann C, et al. Cross-priming of CD8+ T cells stimulated by virus-induced type I interferon. Nat Immunol. 2003;4(10):1009–1015. doi:10.1038/ni978.
  • Johnson LM, Scott P. STAT1 expression in dendritic cells, but not T cells, is required for immunity to Leishmania major. J Immunol. 2007;178(11):7259–7266. doi:10.4049/jimmunol.178.11.7259.
  • Diamond MS, Kinder M, Matsushita H, et al. Type I interferon is selectively required by dendritic cells for immune rejection of tumors. J Exp Med. 2011;208(10):1989–2003. doi:10.1084/jem.20101158.
  • Pilz A, Kratky W, Stockinger S, et al. Dendritic cells require STAT-1 phosphorylated at its transactivating domain for the induction of peptide-specific CTL. J Immunol. 2009;183(4):2286–2293. doi:10.4049/jimmunol.0901383.
  • Kernbauer E, Maier V, Stoiber D, et al. Conditional Stat1 ablation reveals the importance of interferon signaling for immunity to Listeria monocytogenes infection. PLoS Pathog. 2012;8(6):e1002763. doi:10.1371/journal.ppat.1002763.
  • Horejs-Hoeck J, Schwarz H, Lamprecht S, et al. Dendritic cells activated by IFN-γ/STAT1 express IL-31 receptor and release proinflammatory mediators upon IL-31 treatment. J Immunol. 2012;188(11):5319–5326. doi:10.4049/jimmunol.1101044.
  • Takauji R, Iho S, Takatsuka H, et al. CpG-DNA-induced IFN-alpha production involves p38 MAPK-dependent STAT1 phosphorylation in human plasmacytoid dendritic cell precursors. J Leukoc Biol. 2002;72(5):1011–1019.
  • Qiu CC, Kotredes KP, Cremers T, et al. Targeted Stat2 deletion in conventional dendritic cells impairs CTL responses but does not affect antibody production. Oncoimmunology. 2020;10(1):1860477. doi:10.1080/2162402X.2020.1860477.
  • Xu J, Lee MH, Chakhtoura M, et al. STAT2 is required for TLR-induced murine dendritic cell activation and cross-presentation. J Immunol. 2016;197(1):326–336. doi:10.4049/jimmunol.1500152.
  • Chen LS, Wei PC, Liu T, Kao CH, Pai LM, Lee CK. STAT2 hypomorphic mutant mice display impaired dendritic cell development and antiviral response. J Biomed Sci. 2009;16(1):22. doi:10.1186/1423-0127-16-22.
  • Yue C, Xu J, Tan Estioko MD, et al. Host STAT2/type I interferon axis controls tumor growth. Int J Cancer. 2015;136(1):117–126. doi:10.1002/ijc.29004.
  • Hahm B, Trifilo MJ, Zuniga EI, Oldstone MB. Viruses evade the immune system through type I interferon-mediated STAT2-dependent, but STAT1-independent, signaling. Immunity. 2005;22(2):247–257. doi:10.1016/j.immuni.2005.01.005.
  • Wang S, Chen F, Tang L. IL-32 promotes breast cancer cell growth and invasiveness. Oncol Lett. 2015;9(1):305–307. doi:10.3892/ol.2014.2641.
  • Park SJ, Nakagawa T, Kitamura H, et al. IL-6 regulates in vivo dendritic cell differentiation through STAT3 activation. J Immunol. 2004;173(6):3844–3854. doi:10.4049/jimmunol.173.6.3844.
  • Li HS, Yang CY, Nallaparaju KC, et al. The signal transducers STAT5 and STAT3 control expression of Id2 and E2-2 during dendritic cell development. Blood. 2012;120(22):4363–4373. doi:10.1182/blood-2012-07-441311.
  • Laouar Y, Welte T, Fu XY, Flavell RA. STAT3 is required for Flt3L-dependent dendritic cell differentiation. Immunity. 2003;19(6):903–912. doi:10.1016/s1074-7613(03)00332-7.
  • Farren MR, Carlson LM, Netherby CS, et al. Tumor-induced STAT3 signaling in myeloid cells impairs dendritic cell generation by decreasing PKCβII abundance. Sci Signal. 2014;7(313):ra16. doi:10.1126/scisignal.2004656.
  • Jin J, Li Y, Zhao Q, Chen Y, Fu S, Wu J. Coordinated regulation of immune contexture: crosstalk between STAT3 and immune cells during breast cancer progression. Cell Commun Signal. 2021;19(1):50. doi:10.1186/s12964-021-00705-2.
  • Kamphorst AO, Wieland A, Nasti T, et al. Rescue of exhausted CD8 T cells by PD-1-targeted therapies is CD28-dependent. Science. 2017;355(6332):1423–1427. doi:10.1126/science.aaf0683.
  • Melillo JA, Song L, Bhagat G, et al. Dendritic cell (DC)-specific targeting reveals Stat3 as a negative regulator of DC function. J Immunol. 2010;184(5):2638–2645. doi:10.4049/jimmunol.0902960.
  • Esashi E, Wang YH, Perng O, Qin XF, Liu YJ, Watowich SS. The signal transducer STAT5 inhibits plasmacytoid dendritic cell development by suppressing transcription factor IRF8. Immunity. 2008;28(4):509–520. doi:10.1016/j.immuni.2008.02.013.
  • Welte T, Zhang SS, Wang T, et al. STAT3 deletion during hematopoiesis causes Crohn’s disease-like pathogenesis and lethality: a critical role of STAT3 in innate immunity. Proc Natl Acad Sci U S A. 2003;100(4):1879–1884. doi:10.1073/pnas.0237137100.
  • Chrisikos TT, Zhou Y, Li HS, et al. STAT3 inhibits CD103(+) cDC1 vaccine efficacy in murine breast cancer. Cancers (Basel). 2020;12(1):128. doi:10.3390/cancers12010128.
  • Torres-Aguilar H, Aguilar-Ruiz SR, González-Pérez G, et al. Tolerogenic dendritic cells generated with different immunosuppressive cytokines induce antigen-specific anergy and regulatory properties in memory CD4+ T cells. J Immunol. 2010;184(4):1765–1775. doi:10.4049/jimmunol.0902133.
  • Wölfle SJ, Strebovsky J, Bartz H, et al. PD-L1 expression on tolerogenic APCs is controlled by STAT-3. Eur J Immunol. 2011;41(2):413–424. doi:10.1002/eji.201040979.
  • Verginis P, Li HS, Carayanniotis G. Tolerogenic semimature dendritic cells suppress experimental autoimmune thyroiditis by activation of thyroglobulin-specific CD4 + CD25+ T cells. J Immunol. 2005;174(11):7433–7439. doi:10.4049/jimmunol.174.11.7433.
  • Hirata N, Yanagawa Y, Iwabuchi K, Onoé K. Selective regulation of interleukin-10 production via Janus kinase pathway in murine conventional dendritic cells. Cell Immunol. 2009;258(1):9–17. doi:10.1016/j.cellimm.2009.03.006.
  • Jahrsdörfer B, Vollmer A, Blackwell SE, et al. Granzyme B produced by human plasmacytoid dendritic cells suppresses T-cell expansion. Blood. 2010;115(6):1156–1165. doi:10.1182/blood-2009-07-235382.
  • Frucht DM, Aringer M, Galon J, et al. Stat4 is expressed in activated peripheral blood monocytes, dendritic cells, and macrophages at sites of Th1-mediated inflammation. J Immunol. 2000;164(9):4659–4664. doi:10.4049/jimmunol.164.9.4659.
  • Fukao T, Frucht DM, Yap G, Gadina M, O'Shea JJ, Koyasu S. Inducible expression of Stat4 in dendritic cells and macrophages and its critical role in innate and adaptive immune responses. J Immunol. 2001;166(7):4446–4455. doi:10.4049/jimmunol.166.7.4446.
  • Remoli ME, Ragimbeau J, Giacomini E, et al. NF-{kappa}B is required for STAT-4 expression during dendritic cell maturation. J Leukoc Biol. 2007;81(1):355–363. doi:10.1189/jlb.0506319.
  • Tamura T, Tailor P, Yamaoka K, et al. IFN regulatory factor-4 and -8 govern dendritic cell subset development and their functional diversity. J Immunol. 2005;174(5):2573–2581. doi:10.4049/jimmunol.174.5.2573.
  • Shortman K, Naik SH. Steady-state and inflammatory dendritic-cell development. Nat Rev Immunol. 2007;7(1):19–30. doi:10.1038/nri1996.
  • Zenke M, Hieronymus T. Towards an understanding of the transcription factor network of dendritic cell development. Trends Immunol. 2006;27(3):140–145. doi:10.1016/j.it.2005.12.007.
  • Suzuki S, Honma K, Matsuyama T, et al. Critical roles of interferon regulatory factor 4 in CD11bhighCD8alpha- dendritic cell development. Proc Natl Acad Sci U S A. 2004;101(24):8981–8986. doi:10.1073/pnas.0402139101.
  • Iwasaki-Arai J, Iwasaki H, Miyamoto T, Watanabe S, Akashi K. Enforced granulocyte/macrophage colony-stimulating factor signals do not support lymphopoiesis, but instruct lymphoid to myelomonocytic lineage conversion. J Exp Med. 2003;197(10):1311–1322. doi:10.1084/jem.20021843.
  • Hacker C, Kirsch RD, Ju XS, et al. Transcriptional profiling identifies Id2 function in dendritic cell development. Nat Immunol. 2003;4(4):380–386. doi:10.1038/ni903.
  • Cisse B, Caton ML, Lehner M, et al. Transcription factor E2-2 is an essential and specific regulator of plasmacytoid dendritic cell development. Cell. 2008;135(1):37–48. doi:10.1016/j.cell.2008.09.016.
  • Greter M, Helft J, Chow A, et al. GM-CSF controls nonlymphoid tissue dendritic cell homeostasis but is dispensable for the differentiation of inflammatory dendritic cells. Immunity. 2012;36(6):1031–1046. doi:10.1016/j.immuni.2012.03.027.
  • Nagasawa M, Schmidlin H, Hazekamp MG, Schotte R, Blom B. Development of human plasmacytoid dendritic cells depends on the combined action of the basic helix-loop-helix factor E2-2 and the Ets factor Spi-B. Eur J Immunol. 2008;38(9):2389–2400. doi:10.1002/eji.200838470.
  • Bell BD, Kitajima M, Larson RP, et al. The transcription factor STAT5 is critical in dendritic cells for the development of TH2 but not TH1 responses. Nat Immunol. 2013;14(4):364–371. doi:10.1038/ni.2541.
  • Lee S, Shan J, Aldossary H, Gaudreault V, Bazett M, Fixman ED. STAT6 inhibitory peptide reduces dendritic cell migration to the lymph nodes to control Th2 adaptive immunity in the mouse lung. Eur J Immunol. 2019;49(1):157–169. doi:10.1002/eji.201847534.
  • Arima K, Watanabe N, Hanabuchi S, Chang M, Sun SC, Liu YJ. Distinct signal codes generate dendritic cell functional plasticity. Sci Signal. 2010;3(105):ra4. doi:10.1126/scisignal.2000567.
  • Padilla J, Daley E, Chow A, et al. IL-13 regulates the immune response to inhaled antigens. J Immunol. 2005;174(12):8097–8105. doi:10.4049/jimmunol.174.12.8097.
  • Sulczewski FB, Martino LA, da Silva Almeida B, Yamamoto MM, Rosa DS, Boscardin SB. STAT6 signaling pathway controls germinal center responses promoted after antigen targeting to conventional type 2 dendritic cells. Curr Res Immunol. 2021;2:120–131. doi:10.1016/j.crimmu.2021.08.001.
  • Vento-Tormo R, Company C, Rodríguez-Ubreva J, et al. IL-4 orchestrates STAT6-mediated DNA demethylation leading to dendritic cell differentiation. Genome Biol. 2016;17(1):4. doi:10.1186/s13059-015-0863-2.
  • Nieminen JK, Niemi M, Sipponen T, et al. Dendritic cells from Crohn’s disease patients show aberrant STAT1 and STAT3 signaling. PLoS One. 2013;8(8):e70738. doi:10.1371/journal.pone.0070738.
  • Walker JG, Ahern MJ, Coleman M, et al. Expression of Jak3, STAT1, STAT4, and STAT6 in inflammatory arthritis: unique Jak3 and STAT4 expression in dendritic cells in seropositive rheumatoid arthritis. Ann Rheum Dis. 2006;65(2):149–156. doi:10.1136/ard.2005.037929.
  • Parackova Z, Vrabcova P, Zentsova I, et al. Enhanced STAT3 phosphorylation and PD-L1 expression in myeloid dendritic cells indicate impaired IL-27Ralpha signaling in type 1 diabetes. Sci Rep. 2020;10(1):493. doi:10.1038/s41598-020-57507-8.
  • Stone AE, Mitchell A, Brownell J, et al. Hepatitis C virus core protein inhibits interferon production by a human plasmacytoid dendritic cell line and dysregulates interferon regulatory factor-7 and signal transducer and activator of transcription (STAT) 1 protein expression. PLoS One. 2014;9(5):e95627. doi:10.1371/journal.pone.0095627.
  • Ho L-J, Hung L-F, Weng C-Y, et al. Dengue virus type 2 antagonizes IFN-α but not IFN-γ antiviral effect via down-regulating Tyk2-STAT signaling in the human dendritic cell. J Immunol. 2005;174(12):8163–8172. doi:10.4049/jimmunol.174.12.8163.
  • Siddiqui KF, Amir M, Gurram RK, et al. Latency-associated protein Acr1 impairs dendritic cell maturation and functionality: a possible mechanism of immune evasion by Mycobacterium tuberculosis. J Infect Dis. 2014;209(9):1436–1445. doi:10.1093/infdis/jit595.
  • Su H, Peng B, Zhang Z, Liu Z, Zhang Z. The Mycobacterium tuberculosis glycoprotein Rv1016c protein inhibits dendritic cell maturation, and impairs Th1/Th17 responses during mycobacteria infection. Mol Immunol. 2019;109:58–70. doi:10.1016/j.molimm.2019.02.021.
  • Zhu J, Yao K, Guo J, et al. miR-181a and miR-150 regulate dendritic cell immune inflammatory responses and cardiomyocyte apoptosis via targeting JAK 1–STAT 1/c-Fos pathway. J Cell Mol Med. 2017;21(11):2884–2895. doi:10.1111/jcmm.13201.
  • Canavan M, Marzaioli V, McGarry T, et al. Rheumatoid arthritis synovial microenvironment induces metabolic and functional adaptations in dendritic cells. Clin Exp Immunol. 2020;202(2):226–238. doi:10.1111/cei.13479.
  • Cohen PA, Koski GK, Czerniecki BJ, et al. STAT3-and STAT5-dependent pathways competitively regulate the pan-differentiation of CD34pos cells into tumor-competent dendritic cells. Blood, The. Journal of the American Society of Hematology. 2008;112:1832.
  • Nefedova Y, Huang M, Kusmartsev S, et al. Hyperactivation of STAT3 is involved in abnormal differentiation of dendritic cells in cancer. J Immunol. 2004;172(1):464–474. doi:10.4049/jimmunol.172.1.464.
  • Nefedova Y, Cheng P, Gilkes D, et al. Activation of dendritic cells via inhibition of Jak2/STAT3 signaling. J Immunol. 2005;175(7):4338–4346. doi:10.4049/jimmunol.175.7.4338.
  • Li HS, Liu C, Xiao Y, et al. Bypassing STAT3-mediated inhibition of the transcriptional regulator ID2 improves the antitumor efficacy of dendritic cells. Sci Signal. 2016;9(447):ra94. doi:10.1126/scisignal.aaf3957.
  • Alshamsan A, Haddadi A, Hamdy S, et al. STAT3 silencing in dendritic cells by siRNA polyplexes encapsulated in PLGA nanoparticles for the modulation of anticancer immune response. Mol Pharm. 2010;7(5):1643–1654. doi:10.1021/mp100067u.
  • Penafuerte C, Feldhammer M, Mills JR, et al. Downregulation of PTP1B and TC-PTP phosphatases potentiate dendritic cell-based immunotherapy through IL-12/IFNγ signaling. Oncoimmunology. 2017;6(6):e1321185. doi:10.1080/2162402X.2017.1321185.
  • Wang Y, Lu C, Huang H, et al. A lipid-soluble extract of Pinellia pedatisecta Schott orchestrates intratumoral dendritic cell-driven immune activation through SOCS1 signaling in cervical cancer. J Ethnopharmacol. 2021;267:112837. doi:10.1016/j.jep.2020.112837.
  • Brady MT, Miller A, Sait SN, et al. Down-regulation of signal transducer and activator of transcription 3 improves human acute myeloid leukemia-derived dendritic cell function. Leuk Res. 2013;37(7):822–828. doi:10.1016/j.leukres.2013.04.002.
  • Yen J-H, Kong W, Ganea D. IFN-β Inhibits dendritic cell migration through STAT-1–mediated transcriptional suppression of CCR7 and matrix metalloproteinase 9. J Immunol. 2010;184(7):3478–3486. doi:10.4049/jimmunol.0902542.
  • Zhou Y, Leng X, Li H, et al. Tolerogenic dendritic cells induced by BD750 ameliorate proinflammatory T cell responses and experimental autoimmune encephalitis in mice. Mol Med. 2017;23(1):204–214. doi:10.2119/molmed.2016.00110.
  • Marzaioli V, Canavan M, Floudas A, et al. Monocyte-derived dendritic cell differentiation in inflammatory arthritis is regulated by the JAK/STAT axis via NADPH oxidase regulation. Front Immunol. 2020;11:1406. doi:10.3389/fimmu.2020.01406.
  • Zhao H-M, Xu R, Huang X-Y, et al. Curcumin suppressed activation of dendritic cells via JAK/STAT/SOCS signal in mice with experimental colitis. Front Pharmacol. 2016;7:455. doi:10.3389/fphar.2016.00455.
  • Jin W, Huang W, Chen L, et al. Topical application of JAK1/JAK2 inhibitor momelotinib exhibits significant anti-inflammatory responses in DNCB-induced atopic dermatitis model mice. Int J Mol Sci. 2018;19(12):3973. doi:10.3390/ijms19123973.
  • Shi Z, Jiang W, Wang M, et al. Inhibition of JAK/STAT pathway restrains TSLP-activated dendritic cells mediated inflammatory T helper type 2 cell response in allergic rhinitis. Mol Cell Biochem. 2017;430(1-2):161–169. doi:10.1007/s11010-017-2963-7.
  • Donninelli G, Sanseverino I, Purificato C, Gessani S, Gauzzi MC. Dual requirement for STAT signaling in dendritic cell immunobiology. Immunobiology. 2018;223(3):342–347. doi:10.1016/j.imbio.2017.10.049.
  • Cheng J, Deng Y, Yi H, et al. Hepatic carcinoma-associated fibroblasts induce IDO-producing regulatory dendritic cells through IL-6-mediated STAT3 activation. Oncogenesis. 2016;5(2):e198–e198. doi:10.1038/oncsis.2016.7.
  • Wei N, Lin Z, Xu Z, et al. Immunosuppressive effects of tick protein RHcyst-1 on murine bone marrow-derived dendritic cells. Parasit Vectors. 2019;12(1):169. doi:10.1186/s13071-019-3411-1.
  • Yamaoka K. Janus kinase inhibitors for rheumatoid arthritis. Curr Opin Chem Biol. 2016;32:29–33. doi:10.1016/j.cbpa.2016.03.006.
  • Harizi H, Norbert G. Inhibition of IL-6, TNF-alpha, and cyclooxygenase-2 protein expression by prostaglandin E2-induced IL-10 in bone marrow-derived dendritic cells. Cell Immunol. 2004;228(2):99–109. doi:10.1016/j.cellimm.2004.04.003.
  • Pohóczky K, Kun J, Szentes N, et al. Discovery of novel targets in a complex regional pain syndrome mouse model by transcriptomics: TNF and JAK-STAT pathways. Pharmacol Res. 2022;182:106347. doi:10.1016/j.phrs.2022.106347.
  • Steinhagen F, McFarland AP, Rodriguez LG, et al. IRF-5 and NF-κB p50 co-regulate IFN-β and IL-6 expression in TLR9-stimulated human plasmacytoid dendritic cells. Eur J Immunol. 2013;43(7):1896–1906. doi:10.1002/eji.201242792.
  • Uciechowski P, Dempke WCM. Interleukin-6: A masterplayer in the cytokine network. Oncology. 2020;98(3):131–137. doi:10.1159/000505099.
  • Kampan NC, Xiang SD, McNally OM, Stephens AN, Quinn MA, Plebanski M. Immunotherapeutic interleukin-6 or interleukin-6 receptor blockade in cancer: challenges and opportunities. Curr Med Chem. 2018;25(36):4785–4806. doi:10.2174/0929867324666170712160621.
  • Ghoreschi K, Jesson MI, Li X, et al. Modulation of innate and adaptive immune responses by tofacitinib (CP-690,550). J Immunol. 2011;186(7):4234–4243. doi:10.4049/jimmunol.1003668.
  • Li Y, Yuan L, Yang J, et al. Changes in serum cytokines may predict therapeutic efficacy of tofacitinib in rheumatoid arthritis. Mediators Inflamm. 2019;2019:5617431–5617438. doi:10.1155/2019/5617431.
  • Nader A, Mohamed MF, Winzenborg I, et al. Exposure-response analyses of upadacitinib efficacy and safety in phase II and III studies to support benefit-risk assessment in rheumatoid arthritis. Clin Pharmacol Ther. 2020;107(4):994–1003. doi:10.1002/cpt.1671.
  • Xu YD, Cheng M, Shang PP, Yang YQ. Role of IL-6 in dendritic cell functions. J Leukoc Biol. 2022;111(3):695–709. doi:10.1002/JLB.3MR0621-616RR.

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.