Receptor signaling, transcriptional, and metabolic regulation of T cell exhaustion

References

• Wolchok JD, Chiarion-Sileni V, Gonzalez R, Rutkowski P, Grob -J-J, Cowey CL, Lao CD, Wagstaff J, Schadendorf D, Ferrucci PF. Overall survival with combined nivolumab and ipilimumab in advanced melanoma. N Engl J Med. 2017 Oct 5;377(14):1345–18. doi:10.1056/NEJMoa1709684.
   PubMed Web of Science ®Google Scholar
• Pai‐Scherf L, Blumenthal GM, Li H, Subramaniam S, Mishra‐Kalyani PS, He K, Zhao H, Yu J, Paciga M, Goldberg KB. FDA approval summary: pembrolizumab for treatment of metastatic non-small cell lung cancer: first-line therapy and beyond. The Oncologist. 2017 Nov;22(11):1392–1399. doi:10.1634/theoncologist.2017-0078.
   PubMed Web of Science ®Google Scholar
• Sul J, Blumenthal GM, Jiang X, He K, Keegan P, Pazdur R. FDA approval summary: pembrolizumab for the treatment of patients with metastatic non-small cell lung cancer whose tumors express programmed death-ligand 1. The Oncologist. 2016 May;21(5):643–650. doi:10.1634/theoncologist.2015-0498.
   PubMed Web of Science ®Google Scholar
• Kato S, Goodman A, Walavalkar V, Barkauskas DA, Sharabi A, Kurzrock R. Hyperprogressors after immunotherapy: analysis of genomic alterations associated with accelerated growth rate. Clin Cancer Res. 2017 Aug 1;23(15):4242–4250. doi:10.1158/1078-0432.CCR-16-3133.
   PubMed Web of Science ®Google Scholar
• Borghaei H, Paz-Ares L, Horn L, Spigel DR, Steins M, Ready NE, Chow LQ, Vokes EE, Felip E, Holgado E. Nivolumab versus docetaxel in advanced nonsquamous non–small-cell lung cancer. N Engl J Med. 2015 Oct 22;373(17):1627–1639. doi:10.1056/NEJMoa1507643.
   PubMed Web of Science ®Google Scholar
• Robert C, Long GV, Brady B, Dutriaux C, Maio M, Mortier L, Hassel JC, Rutkowski P, McNeil C, Kalinka-Warzocha E. Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med. 2015 Jan 22;372(4):320–330. doi:10.1056/NEJMoa1412082.
   PubMed Web of Science ®Google Scholar
• Yan B, Noone A-M, Yee C, Banerjee M, Schwartz K, Simon MS. Racial differences in colorectal cancer survival in the detroit metropolitan area. Cancer. 2009 Aug 15;115(16):3791–3800. doi:10.1002/cncr.24408.
   PubMed Web of Science ®Google Scholar
• Hashimoto M, Kamphorst AO, Im SJ, Kissick HT, Pillai RN, Ramalingam SS, Araki K, Ahmed R. CD8 T cell exhaustion in chronic infection and cancer: opportunities for interventions. Annu Rev Med. 2018 Jan 29;69(1):301–318. doi:10.1146/annurev-med-012017-043208.
   PubMed Web of Science ®Google Scholar
• Pauken KE, Wherry EJ. Overcoming T cell exhaustion in infection and cancer. Trends Immunol. 2015 Apr;36(4):265–276. doi:10.1016/j.it.2015.02.008.
   PubMed Web of Science ®Google Scholar
• Philip M, Schietinger A. Heterogeneity and fate choice: T cell exhaustion in cancer and chronic infections. Curr Opin Immunol. 2019 Jun;58:98–103. doi:10.1016/j.coi.2019.04.014.
   PubMed Web of Science ®Google Scholar
• Picarda E, Ren X, Zang X. Tumor cholesterol up, T cells down. Cell Metab. 2019 Jul 2;30(1):12–13. doi:10.1016/j.cmet.2019.06.007.
   PubMed Web of Science ®Google Scholar
• Buchholz VR, Flossdorf M, Hensel I, Kretschmer L, Weissbrich B, Graf P, Verschoor A, Schiemann M, Hofer T, Busch DH. Disparate individual fates compose robust CD8+ T cell immunity. Science. 2013 May 3;340(6132):630–635. doi:10.1126/science.1235454.
   PubMed Web of Science ®Google Scholar
• Gerlach C, Rohr JC, Perie L, van Rooij N, van Heijst JWJ, Velds A, Urbanus J, Naik SH, Jacobs H, Beltman JB. Heterogeneous differentiation patterns of individual CD8+ T cells. Science. 2013 May 3;340(6132):635–639. doi:10.1126/science.1235487.
   PubMed Web of Science ®Google Scholar
• Kakaradov B, Arsenio J, Widjaja CE, He Z, Aigner S, Metz PJ, Yu B, Wehrens EJ, Lopez J, Kim SH. Early transcriptional and epigenetic regulation of CD8+ T cell differentiation revealed by single-cell RNA sequencing. Nat Immunol. 2017 Apr;18(4):422–432. doi:10.1038/ni.3688.
   PubMed Web of Science ®Google Scholar
• Joffre OP, Segura E, Savina A, Amigorena S. Cross-presentation by dendritic cells. Nat Rev Immunol. 2012 Jul 13;12(8):557–569. doi:10.1038/nri3254.
   PubMed Web of Science ®Google Scholar
• Kaech SM, Cui W. Transcriptional control of effector and memory CD8+ T cell differentiation. Nat Rev Immunol. 2012 Nov;12(11):749–761. doi:10.1038/nri3307.
   PubMed Web of Science ®Google Scholar
• Wherry EJ, Ahmed R. Memory CD8 T-cell differentiation during viral infection. J Virol. 2004 Jun;78(11):5535–5545. doi:10.1128/JVI.78.11.5535-5545.2004.
   PubMed Web of Science ®Google Scholar
• Farber DL, Yudanin NA, Restifo NP. Human memory T cells: generation, compartmentalization and homeostasis. Nat Rev Immunol. 2014 Jan;14(1):24–35. doi:10.1038/nri3567.
   PubMed Web of Science ®Google Scholar
• Remakus S, Sigal LJ. Memory CD8(+) T cell protection. Adv Exp Med Biol. 2013;785:77–86.
   PubMed Web of Science ®Google Scholar
• Romero P, Zippelius A, Kurth I, Pittet MJ, Touvrey C, Iancu EM, Corthesy P, Devevre E, Speiser DE, Rufer N. Four functionally distinct populations of human effector-memory CD8+ T lymphocytes. J Immunol. 2007 Apr 1;178(7):4112–4119. doi:10.4049/jimmunol.178.7.4112.
   PubMed Web of Science ®Google Scholar
• Shin H, Blackburn SD, Blattman JN, Wherry EJ. Viral antigen and extensive division maintain virus-specific CD8 T cells during chronic infection. J Exp Med. 2007 Apr 16;204(4):941–949. doi:10.1084/jem.20061937.
   PubMed Web of Science ®Google Scholar
• Wherry EJ, Barber DL, Kaech SM, Blattman JN, Ahmed R. Antigen-independent memory CD8 T cells do not develop during chronic viral infection. Proc Natl Acad Sci U S A. 2004 Nov 9;101(45):16004–16009. doi:10.1073/pnas.0407192101.
   PubMed Web of Science ®Google Scholar
• Giguere J-F, Bounou S, Paquette J-S, Madrenas J, Tremblay MJ. Insertion of host-derived costimulatory molecules CD80 (B7.1) and CD86 (B7.2) into human immunodeficiency virus type 1 affects the virus life cycle. J Virol. 2004 Jun;78(12):6222–6232. doi:10.1128/JVI.78.12.6222-6232.2004.
   PubMed Web of Science ®Google Scholar
• Kedzierska K, Crowe SM. The role of monocytes and macrophages in the pathogenesis of HIV-1 infection. Curr Med Chem. 2002 Nov;9(21):1893–1903. doi:10.2174/0929867023368935.
   PubMed Web of Science ®Google Scholar
• Huang AY, Golumbek P, Ahmadzadeh M, Jaffee E, Pardoll D, Levitsky H. Role of bone marrow-derived cells in presenting MHC class I-restricted tumor antigens. Science. 1994 May 13;264(5161):961–965. doi:10.1126/science.7513904.
   PubMed Web of Science ®Google Scholar
• Gardner A, Ruffell B. Dendritic cells and cancer immunity. Trends Immunol. 2016 Dec;37(12):855–865. doi:10.1016/j.it.2016.09.006.
   PubMed Web of Science ®Google Scholar
• Bottcher JP, Reis ESC. The role of type 1 conventional dendritic cells in cancer immunity. Trends in Cancer. 2018 Nov;4(11):784–792. doi:10.1016/j.trecan.2018.09.001.
   PubMed Web of Science ®Google Scholar
• Saxena M, Bhardwaj N. Re-emergence of dendritic cell vaccines for cancer treatment. Trends in Cancer. 2018 Feb;4(2):119–137. doi:10.1016/j.trecan.2017.12.007.
   PubMed Web of Science ®Google Scholar
• Jadhav RR, Im SJ, Hu B, Hashimoto M, Li P, Lin J-X, Leonard WJ, Greenleaf WJ, Ahmed R, Goronzy JJ. Epigenetic signature of PD-1+ TCF1+ CD8 T cells that act as resource cells during chronic viral infection and respond to PD-1 blockade. Proc Natl Acad Sci U S A. 2019 Jul 9;116(28):14113–14118. doi:10.1073/pnas.1903520116.
   PubMed Web of Science ®Google Scholar
• Im SJ, Hashimoto M, Gerner MY, Lee J, Kissick HT, Burger MC, Shan Q, Hale JS, Lee J, Nasti TH. Defining CD8+ T cells that provide the proliferative burst after PD-1 therapy. Nature. 2016 Sep 15;537(7620):417–421. doi:10.1038/nature19330.
   PubMed Web of Science ®Google Scholar
• Verdeil G. MAF drives CD8 (+)T-cell exhaustion. Oncoimmunology. 2016 Feb;5(2):e1082707. doi:10.1080/2162402X.2015.1082707.
   PubMed Web of Science ®Google Scholar
• Zajac AJ, Blattman JN, Murali-Krishna K, Sourdive DJD, Suresh M, Altman JD, Ahmed R. Viral immune evasion due to persistence of activated T cells without effector function. J Exp Med. 1998 Dec 21;188(12):2205–2213. doi:10.1084/jem.188.12.2205.
   PubMed Web of Science ®Google Scholar
• Kalia V, Sarkar S, Ahmed R. CD8 T-cell memory differentiation during acute and chronic viral infections. Adv Exp Med Biol. 2010;684:79–95.
   PubMed Web of Science ®Google Scholar
• Chen Z, Stelekati E, Kurachi M, Yu S, Cai Z, Manne S, Khan O, Yang X, Wherry EJ. miR-150 regulates memory CD8 T cell differentiation via c-Myb. Cell Rep. 2017 Sep 12;20(11):2584–2597. doi:10.1016/j.celrep.2017.08.060.
   PubMed Web of Science ®Google Scholar
• Chen Z, Ji Z, Ngiow SF. TCF-1-centered transcriptional network drives an effector versus exhausted CD8 T cell-fate decision. Immunity. 2019;Oct 7
   Web of Science ®Google Scholar
• Siddiqui I, Schaeuble K, Chennupati V, Fuertes Marraco SA, Calderon-Copete S, Pais Ferreira D, Carmona SJ, Scarpellino L, Gfeller D, Pradervand S. Intratumoral Tcf1+PD-1+CD8+ T cells with stem-like properties promote tumor control in response to vaccination and checkpoint blockade immunotherapy. Immunity. 2019 Jan 15;50(1):195–211 e10. doi:10.1016/j.immuni.2018.12.021.
   PubMed Web of Science ®Google Scholar
• Balkhi MY, Wittmann G, Xiong F, Junghans RP. YY1 upregulates checkpoint receptors and downregulates type I cytokines in exhausted, chronically stimulated human T cells. iScience. 2018 Apr 27;2:105–122. doi:10.1016/j.isci.2018.03.009.
   PubMed Web of Science ®Google Scholar
• West EE, Jin H-T, Rasheed A-U, Penaloza-MacMaster P, Ha S-J, Tan WG, Youngblood B, Freeman GJ, Smith KA, Ahmed R. PD-L1 blockade synergizes with IL-2 therapy in reinvigorating exhausted T cells. J Clin Invest. 2013 Jun;123(6):2604–2615. doi:10.1172/JCI67008.
   PubMed Web of Science ®Google Scholar
• Kamphorst AO, Wieland A, Nasti T, Yang S, Zhang R, Barber DL, Konieczny BT, Daugherty CZ, Koenig L, Yu K. Rescue of exhausted CD8 T cells by PD-1–targeted therapies is CD28-dependent. Science. 2017 Mar 31;355(6332):1423–1427. doi:10.1126/science.aaf0683.
   PubMed Web of Science ®Google Scholar
• Pauken KE, Sammons MA, Odorizzi PM, Manne S, Godec J, Khan O, Drake AM, Chen Z, Sen DR, Kurachi M. Epigenetic stability of exhausted T cells limits durability of reinvigoration by PD-1 blockade. Science. 2016 Dec 2;354(6316):1160–1165. doi:10.1126/science.aaf2807.
   PubMed Web of Science ®Google Scholar
• Blackburn SD, Shin H, Freeman GJ, Wherry EJ. Selective expansion of a subset of exhausted CD8 T cells by alphaPD-L1 blockade. Proc Natl Acad Sci U S A. 2008 Sep 30;105(39):15016–15021. doi:10.1073/pnas.0801497105.
   PubMed Web of Science ®Google Scholar
• Man K, Gabriel SS, Liao Y, Gloury R, Preston S, Henstridge DC, Pellegrini M, Zehn D, Berberich-Siebelt F, Febbraio MA. Transcription factor IRF4 promotes CD8+ T cell exhaustion and limits the development of memory-like T cells during chronic infection. Immunity. 2017 Dec 19;47(6):1129–1141 e5. doi:10.1016/j.immuni.2017.11.021.
   PubMed Web of Science ®Google Scholar
• Giordano M, Henin C, Maurizio J, Imbratta C, Bourdely P, Buferne M, Baitsch L, Vanhille L, Sieweke MH, Speiser DE. Molecular profiling of CD8 T cells in autochthonous melanoma identifies Maf as driver of exhaustion. Embo J. 2015 Aug 4;34(15):2042–2058. doi:10.15252/embj.201490786.
   PubMed Web of Science ®Google Scholar
• Thangavelu G, Gill RG, Boon L, Ellestad KK, Anderson CC. Control of in vivo collateral damage generated by T cell immunity. J Immunol. 2013 Aug 15;191(4):1686–1691. doi:10.4049/jimmunol.1203240.
   PubMed Web of Science ®Google Scholar
• Bakacs T, Moss RW, Kleef R. Exploiting autoimmunity unleashed by low-dose immune checkpoint blockade to treat advanced cancer. Scand J Immunol. 2019 Oct 7:e12821.
   PubMedGoogle Scholar
• Hellerstein MK, Hoh RA, Hanley MB, Cesar D, Lee D, Neese RA, McCune JM. Subpopulations of long-lived and short-lived T cells in advanced HIV-1 infection. J Clin Invest. 2003 Sep;112(6):956–966. doi:10.1172/JCI200317533.
   PubMed Web of Science ®Google Scholar
• Paley MA, Kroy DC, Odorizzi PM, Johnnidis JB, Dolfi DV, Barnett BE, Bikoff EK, Robertson EJ, Lauer GM, Reiner SL. Progenitor and terminal subsets of CD8+ T cells cooperate to contain chronic viral infection. Science. 2012 Nov 30;338(6111):1220–1225. doi:10.1126/science.1229620.
   PubMed Web of Science ®Google Scholar
• Leong YA, Chen Y, Ong HS, Wu D, Man K, Deleage C, Minnich M, Meckiff BJ, Wei Y, Hou Z. CXCR5+ follicular cytotoxic T cells control viral infection in B cell follicles. Nat Immunol. 2016 Oct;17(10):1187–1196. doi:10.1038/ni.3543.
   PubMed Web of Science ®Google Scholar
• Utzschneider DT, Charmoy M, Chennupati V, Pousse L, Ferreira DP, Calderon-Copete S, Danilo M, Alfei F, Hofmann M, Wieland D. T cell factor 1-expressing memory-like CD8+ T cells sustain the immune response to chronic viral infections. Immunity. 2016 Aug 16;45(2):415–427. doi:10.1016/j.immuni.2016.07.021.
   PubMed Web of Science ®Google Scholar
• Shan Q, Zeng Z, Xing S, Li F, Hartwig SM, Gullicksrud JA, Kurup SP, Van Braeckel-Budimir N, Su Y, Martin MD. The transcription factor Runx3 guards cytotoxic CD8+ effector T cells against deviation towards follicular helper T cell lineage. Nat Immunol. 2017 Aug;18(8):931–939. doi:10.1038/ni.3773.
   PubMed Web of Science ®Google Scholar
• Wang D, Diao H, Getzler AJ, Rogal W, Frederick MA, Milner J, Yu B, Crotty S, Goldrath AW, Pipkin ME. The transcription factor Runx3 establishes chromatin accessibility of cis-regulatory landscapes that drive memory cytotoxic T lymphocyte formation. Immunity. 2018 Apr 17;48(4):659–674 e6. doi:10.1016/j.immuni.2018.03.028.
   PubMed Web of Science ®Google Scholar
• Cruz-Guilloty F, Pipkin ME, Djuretic IM, Levanon D, Lotem J, Lichtenheld MG, Groner Y, Rao A. Runx3 and T-box proteins cooperate to establish the transcriptional program of effector CTLs. J Exp Med. 2009 Jan 16;206(1):51–59. doi:10.1084/jem.20081242.
   PubMed Web of Science ®Google Scholar
• Thommen DS, Koelzer VH, Herzig P, Roller A, Trefny M, Dimeloe S, Kiialainen A, Hanhart J, Schill C, Hess C. A transcriptionally and functionally distinct PD-1+ CD8+ T cell pool with predictive potential in non-small-cell lung cancer treated with PD-1 blockade. Nat Med. 2018 Jul;24(7):994–1004. doi:10.1038/s41591-018-0057-z.
   PubMed Web of Science ®Google Scholar
• Allie SR, Zhang W, Fuse S, Usherwood EJ. Programmed death 1 regulates development of central memory CD8 T cells after acute viral infection. J Immunol. 2011 Jun 1;186(11):6280–6286. doi:10.4049/jimmunol.1003870.
   PubMed Web of Science ®Google Scholar
• Shin H, Wherry EJ. CD8 T cell dysfunction during chronic viral infection. Curr Opin Immunol. 2007 Aug;19(4):408–415. doi:10.1016/j.coi.2007.06.004.
   PubMed Web of Science ®Google Scholar
• Nguyen LT, Ohashi PS. Clinical blockade of PD1 and LAG3–potential mechanisms of action. Nat Rev Immunol. 2015 Jan;15(1):45–56. doi:10.1038/nri3790.
   PubMed Web of Science ®Google Scholar
• Rosenberg SA, Yang JC, Sherry RM, Kammula US, Hughes MS, Phan GQ, Citrin DE, Restifo NP, Robbins PF, Wunderlich JR. Durable complete responses in heavily pretreated patients with metastatic melanoma using T-cell transfer immunotherapy. Clin Cancer Res. 2011 Jul 1;17(13):4550–4557. doi:10.1158/1078-0432.CCR-11-0116.
   PubMed Web of Science ®Google Scholar
• Emtage PC, Lo AS, Gomes EM, Liu DL, Gonzalo-Daganzo RM, Junghans RP. Second-generation anti-carcinoembryonic antigen designer T cells resist activation-induced cell death, proliferate on tumor contact, secrete cytokines, and exhibit superior antitumor activity in vivo: a preclinical evaluation. Clin Cancer Res. 2008 Dec 15;14(24):8112–8122. doi:10.1158/1078-0432.CCR-07-4910.
   PubMed Web of Science ®Google Scholar
• Rosenberg SA, Mule JJ, Spiess PJ, Reichert CM, Schwarz SL. Regression of established pulmonary metastases and subcutaneous tumor mediated by the systemic administration of high-dose recombinant interleukin 2. J Exp Med. 1985 May 1;161(5):1169–1188. doi:10.1084/jem.161.5.1169.
   PubMed Web of Science ®Google Scholar
• Wherry EJ, Blattman JN, Murali-Krishna K, van der Most R, Ahmed R. Viral persistence alters CD8 T-cell immunodominance and tissue distribution and results in distinct stages of functional impairment. J Virol. 2003 Apr;77(8):4911–4927. doi:10.1128/JVI.77.8.4911-4927.2003.
   PubMed Web of Science ®Google Scholar
• Lo AS, Ma Q, Liu DL, Junghans RP. Anti-GD3 chimeric sFv-CD28/T-cell receptor zeta designer T cells for treatment of metastatic melanoma and other neuroectodermal tumors. Clin Cancer Res. 2010 May 15;16(10):2769–2780. doi:10.1158/1078-0432.CCR-10-0043.
   PubMed Web of Science ®Google Scholar
• Liao W, Lin J-X, Leonard WJ. Interleukin-2 at the crossroads of effector responses, tolerance, and immunotherapy. Immunity. 2013 Jan 24;38(1):13–25. doi:10.1016/j.immuni.2013.01.004.
   PubMed Web of Science ®Google Scholar
• Hu CY, Zhang YH, Wang T, Chen L, Gong ZH, Wan YS, Li QJ, Li YS, Zhu B. Interleukin-2 reverses CD8(+)T cell exhaustion in clinical malignant pleural effusion of lung cancer. Clin Exp Immunol. 2016 Oct;186(1):106–114. doi:10.1111/cei.12845.
   PubMed Web of Science ®Google Scholar
• MacIver NJ, Michalek RD, Rathmell JC. Metabolic regulation of T lymphocytes. Annu Rev Immunol. 2013;31(1):259–283. doi:10.1146/annurev-immunol-032712-095956.
   PubMed Web of Science ®Google Scholar
• Krauss S, Brand MD, Buttgereit F. Signaling takes a breath – new quantitative perspectives on bioenergetics and signal transduction. Immunity. 2001 Oct;15(4):497–502. doi:10.1016/S1074-7613(01)00205-9.
   PubMed Web of Science ®Google Scholar
• Vander Heiden MG, Cantley LC, Thompson CB. Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science. 2009 May 22;324(5930):1029–1033. doi:10.1126/science.1160809.
   PubMed Web of Science ®Google Scholar
• Warburg O. On the origin of cancer cells. Science. 1956 Feb 24;123(3191):309–314. doi:10.1126/science.123.3191.309.
   PubMed Web of Science ®Google Scholar
• Pearce EL, Pearce EJ. Metabolic pathways in immune cell activation and quiescence. Immunity. 2013 Apr 18;38(4):633–643. doi:10.1016/j.immuni.2013.04.005.
   PubMed Web of Science ®Google Scholar
• van der Windt GW, Everts B, Chang C-H, Curtis J, Freitas T, Amiel E, Pearce E, Pearce E. Mitochondrial respiratory capacity is a critical regulator of CD8+ T cell memory development. Immunity. 2012 Jan 27;36(1):68–78. doi:10.1016/j.immuni.2011.12.007.
   PubMed Web of Science ®Google Scholar
• Wherry EJ, Ha S-J, Kaech SM, Haining WN, Sarkar S, Kalia V, Subramaniam S, Blattman JN, Barber DL, Ahmed R. Molecular signature of CD8+ T cell exhaustion during chronic viral infection. Immunity. 2007 Oct;27(4):670–684. doi:10.1016/j.immuni.2007.09.006.
   PubMed Web of Science ®Google Scholar
• Bengsch B, Johnson AL, Kurachi M, Odorizzi PM, Pauken KE, Attanasio J, Stelekati E, McLane LM, Paley MA, Delgoffe GM. Bioenergetic insufficiencies due to metabolic alterations regulated by the inhibitory receptor PD-1 are an early driver of CD8(+) T cell exhaustion. Immunity. 2016 Aug 16;45(2):358–373. doi:10.1016/j.immuni.2016.07.008.
   PubMed Web of Science ®Google Scholar
• Scharping NE, Menk AV, Moreci RS, Whetstone RD, Dadey RE, Watkins SC, Ferris RL, Delgoffe GM. The tumor microenvironment represses T cell mitochondrial biogenesis to drive intratumoral T cell metabolic insufficiency and dysfunction. Immunity. 2016 Aug 16;45(2):374–388. doi:10.1016/j.immuni.2016.07.009.
   PubMed Web of Science ®Google Scholar
• Austin S, St-Pierre J. PGC1alpha and mitochondrial metabolism - emerging concepts and relevance in ageing and neurodegenerative disorders. J Cell Sci. 2012 Nov 1;125(21):4963–4971. doi:10.1242/jcs.113662.
   PubMed Web of Science ®Google Scholar
• Dankort D, Curley DP, Cartlidge RA, Nelson B, Karnezis AN, Damsky Jr WE, You MJ, DePinho RA, McMahon M, Bosenberg M. Braf(V600E) cooperates with Pten loss to induce metastatic melanoma. Nat Genet. 2009 May;41(5):544–552. doi:10.1038/ng.356.
   PubMed Web of Science ®Google Scholar
• Chang C-H, Qiu J, O’Sullivan D, Buck M, Noguchi T, Curtis J, Chen Q, Gindin M, Gubin M, van der Windt GW. Metabolic competition in the tumor microenvironment is a driver of cancer progression. Cell. 2015 Sep 10;162(6):1229–1241. doi:10.1016/j.cell.2015.08.016.
   PubMed Web of Science ®Google Scholar
• McKinney EF, Smith KGC. Metabolic exhaustion in infection, cancer and autoimmunity. Nat Immunol. 2018 Mar;19(3):213–221. doi:10.1038/s41590-018-0045-y.
   PubMed Web of Science ®Google Scholar
• Ho P-C, Bihuniak JD, Macintyre AN, Staron M, Liu X, Amezquita R, Tsui Y-C, Cui G, Micevic G, Perales J. Phosphoenolpyruvate is a metabolic checkpoint of anti-tumor T cell responses. Cell. 2015 Sep 10;162(6):1217–1228. doi:10.1016/j.cell.2015.08.012.
   PubMed Web of Science ®Google Scholar
• Crawford A, Angelosanto JM, Kao C, Doering T, Odorizzi P, Barnett B, Wherry E. Molecular and transcriptional basis of CD4+ T cell dysfunction during chronic infection. Immunity. 2014 Feb 20;40(2):289–302. doi:10.1016/j.immuni.2014.01.005.
   PubMed Web of Science ®Google Scholar
• Baitsch L, Baumgaertner P, Devevre E, Raghav SK, Legat A, Barba L, Wieckowski S, Bouzourene H, Deplancke B, Romero P. Exhaustion of tumor-specific CD8(+) T cells in metastases from melanoma patients. J Clin Invest. 2011 Jun;121(6):2350–2360. doi:10.1172/JCI46102.
   PubMed Web of Science ®Google Scholar
• Mognol GP, Spreafico R, Wong V, Scott-Browne JP, Togher S, Hoffmann A, Hogan PG, Rao A, Trifari S. Exhaustion-associated regulatory regions in CD8(+) tumor-infiltrating T cells. Proc Natl Acad Sci U S A. 2017 Mar 28;114(13):E2776–E2785. doi:10.1073/pnas.1620498114.
   PubMed Web of Science ®Google Scholar
• Hadrup SR. The antigen specific composition of melanoma tumor infiltrating lymphocytes? Oncoimmunology. 2012 Sep 1;1(6):935–936. doi:10.4161/onci.20303.
   PubMed Web of Science ®Google Scholar
• Cohen CJ, Gartner JJ, Horovitz-Fried M, Shamalov K, Trebska-McGowan K, Bliskovsky VV, Parkhurst MR, Ankri C, Prickett TD, Crystal JS. Isolation of neoantigen-specific T cells from tumor and peripheral lymphocytes. J Clin Invest. 2015 Oct 01;125(10):3981–3991. doi:10.1172/JCI82416.
   PubMed Web of Science ®Google Scholar
• Robbins PF, Lu Y-C, El-Gamil M, Li YF, Gross C, Gartner J, Lin JC, Teer JK, Cliften P, Tycksen E. Mining exomic sequencing data to identify mutated antigens recognized by adoptively transferred tumor-reactive T cells. Nat Med. 2013 Jun;19(6):747–752. doi:10.1038/nm.3161.
   PubMed Web of Science ®Google Scholar
• Lu Y-C, Yao X, Crystal JS, Li YF, El-Gamil M, Gross C, Davis L, Dudley ME, Yang JC, Samuels Y. Efficient identification of mutated cancer antigens recognized by T cells associated with durable tumor regressions. Clin Cancer Res. 2014 Jul 01;20(13):3401–3410. doi:10.1158/1078-0432.CCR-14-0433.
   PubMed Web of Science ®Google Scholar
• Coulie PG, Van den Eynde BJ, van der Bruggen P, Boon T. Tumour antigens recognized by T lymphocytes: at the core of cancer immunotherapy. Nat Rev Cancer. 2014 Feb;14(2):135–146. doi:10.1038/nrc3670.
   PubMed Web of Science ®Google Scholar
• Stevanovic S, Pasetto A, Helman SR, Gartner JJ, Prickett TD, Howie B, Robins HS, Robbins PF, Klebanoff CA, Rosenberg SA. Landscape of immunogenic tumor antigens in successful immunotherapy of virally induced epithelial cancer. Science. 2017 Apr 14;356(6334):200–205. doi:10.1126/science.aak9510.
   PubMed Web of Science ®Google Scholar
• Perrotti D, Jamieson C, Goldman J, Skorski T. Chronic myeloid leukemia: mechanisms of blastic transformation. J Clin Invest. 2010 Jul 1;120(7):2254–2264. doi:10.1172/JCI41246.
   PubMed Web of Science ®Google Scholar
• Bjorklund ÅK, Forkel M, Picelli S, Konya V, Theorell J, Friberg D, Sandberg R, Mjösberg J. The heterogeneity of human CD127+ innate lymphoid cells revealed by single-cell RNA sequencing. Nat Immunol. 2016 Apr;17(4):451–460. doi:10.1038/ni.3368.
   PubMed Web of Science ®Google Scholar
• Villani AC, Shekhar K. Single-cell RNA sequencing of human T cells. Methods Mol Biol. 2017;1514:203–239.
   PubMedGoogle Scholar
• Proserpio V, Piccolo A, Haim-Vilmovsky L, Kar G, Lönnberg T, Svensson V, Pramanik J, Natarajan KN, Zhai W, Zhang X. Single-cell analysis of CD4+ T-cell differentiation reveals three major cell states and progressive acceleration of proliferation. Genome Biol. 2016 May 12;17(1):103. doi:10.1186/s13059-016-0957-5.
   PubMedGoogle Scholar
• Singer M, Wang C, Cong L, Marjanovic ND, Kowalczyk MS, Zhang H, Nyman J, Sakuishi K, Kurtulus S, Gennert D. A distinct gene module for dysfunction uncoupled from activation in tumor-infiltrating T cells. Cell. 2017 Nov 16;171(5):1221–1223. doi:10.1016/j.cell.2017.11.006.
   PubMed Web of Science ®Google Scholar
• Concepcion AR, Vaeth M, Wagner LE 2nd, Eckstein M, Hecht L, Yang J, Crottes D, Seidl M, Shin HP, Weidinger C. Store-operated Ca2+ entry regulates Ca2+-activated chloride channels and eccrine sweat gland function. J Clin Invest. 2016 Nov 1;126(11):4303–4318. doi:10.1172/JCI89056.
   PubMed Web of Science ®Google Scholar
• Martinez GJ, Pereira RM, Aijo T, Kim EY, Marangoni F, Pipkin ME, Togher S, Heissmeyer V, Zhang YC, Crotty S. The transcription factor NFAT promotes exhaustion of activated CD8 + T cells. Immunity. 2015 Feb 17;42(2):265–278. doi:10.1016/j.immuni.2015.01.006.
   PubMed Web of Science ®Google Scholar
• Li P, Spolski R, Liao W, Wang L, Murphy TL, Murphy KM, Leonard WJ. BATF–JUN is critical for IRF4-mediated transcription in T cells. Nature. 2012 Oct 25;490(7421):543–546. doi:10.1038/nature11530.
   PubMed Web of Science ®Google Scholar
• Brooks DG, Lee AM, Elsaesser H, McGavern DB, Oldstone MBA. IL-10 blockade facilitates DNA vaccine-induced T cell responses and enhances clearance of persistent virus infection. J Exp Med. 2008 Mar 17;205(3):533–541. doi:10.1084/jem.20071948.
   PubMed Web of Science ®Google Scholar
• Ejrnaes M, Filippi CM, Martinic MM, Ling EM, Togher LM, Crotty S, von Herrath MG. Resolution of a chronic viral infection after interleukin-10 receptor blockade. J Exp Med. 2006 Oct 30;203(11):2461–2472. doi:10.1084/jem.20061462.
   PubMed Web of Science ®Google Scholar
• Penaloza-MacMaster P, Kamphorst AO, Wieland A, Araki K, Iyer SS, West EE, O’Mara L, Yang S, Konieczny BT, Sharpe AH. Interplay between regulatory T cells and PD-1 in modulating T cell exhaustion and viral control during chronic LCMV infection. J Exp Med. 2014 Aug 25;211(9):1905–1918. doi:10.1084/jem.20132577.
   PubMed Web of Science ®Google Scholar
• Intlekofer AM, Takemoto N, Kao C, Banerjee A, Schambach F, Northrop JK, Shen H, Wherry EJ, Reiner SL. Requirement for T-bet in the aberrant differentiation of unhelped memory CD8+ T cells. J Exp Med. 2007 Sep 3;204(9):2015–2021. doi:10.1084/jem.20070841.
   PubMed Web of Science ®Google Scholar
• Pearce EL, Mullen AC, Martins GA. Control of effector CD8+ T cell function by the transcription factor Eomesodermin. Science. 2003 Nov 7;302(5647):1041–1043. doi:10.1126/science.1090148.
   PubMed Web of Science ®Google Scholar
• Sullivan BM, Juedes A, Szabo SJ, von Herrath M, Glimcher LH. Antigen-driven effector CD8 T cell function regulated by T-bet. Proc Natl Acad Sci U S A. 2003 Dec 23;100(26):15818–15823. doi:10.1073/pnas.2636938100.
   PubMed Web of Science ®Google Scholar
• Glimcher LH, Townsend MJ, Sullivan BM, Lord GM. Recent developments in the transcriptional regulation of cytolytic effector cells. Nat Rev Immunol. 2004 Nov;4(11):900–911. doi:10.1038/nri1490.
   PubMed Web of Science ®Google Scholar
• Kao C, Oestreich KJ, Paley MA, Crawford A, Angelosanto JM, Ali MAA, Intlekofer AM, Boss JM, Reiner SL, Weinmann AS. Transcription factor T-bet represses expression of the inhibitory receptor PD-1 and sustains virus-specific CD8+ T cell responses during chronic infection. Nat Immunol. 2011 May 29;12(7):663–671. doi:10.1038/ni.2046.
   PubMed Web of Science ®Google Scholar
• Joshi NS, Cui W, Chandele A, Lee HK, Urso DR, Hagman J, Gapin L, Kaech SM. Inflammation directs memory precursor and short-lived effector CD8+ T cell fates via the graded expression of T-bet transcription factor. Immunity. 2007 Aug;27(2):281–295. doi:10.1016/j.immuni.2007.07.010.
   PubMed Web of Science ®Google Scholar
• Joshi NS, Cui W, Dominguez CX, Chen JH, Hand TW, Kaech SM. Increased numbers of preexisting memory CD8 T cells and decreased T-bet expression can restrain terminal differentiation of secondary effector and memory CD8 T cells. J Immunol. 2011 Oct 15;187(8):4068–4076. doi:10.4049/jimmunol.1002145.
   PubMed Web of Science ®Google Scholar
• Buggert M, Tauriainen J, Yamamoto T, Frederiksen J, Ivarsson MA, Michaëlsson J, Lund O, Hejdeman B, Jansson M, Sönnerborg A. T-bet and Eomes are differentially linked to the exhausted phenotype of CD8+ T cells in HIV infection. PLoS Pathog. 2014 Jul;10(7):e1004251. doi:10.1371/journal.ppat.1004251.
   PubMed Web of Science ®Google Scholar
• Kallies A, Xin A, Belz GT, Nutt SL. Blimp-1 transcription factor is required for the differentiation of effector CD8+ T cells and memory responses. Immunity. 2009 Aug 21;31(2):283–295. doi:10.1016/j.immuni.2009.06.021.
   PubMed Web of Science ®Google Scholar
• Rutishauser RL, Martins GA, Kalachikov S, Chandele A, Parish IA, Meffre E, Jacob J, Calame K, Kaech SM. Transcriptional repressor Blimp-1 promotes CD8+ T cell terminal differentiation and represses the acquisition of central memory T cell properties. Immunity. 2009 Aug 21;31(2):296–308. doi:10.1016/j.immuni.2009.05.014.
   PubMed Web of Science ®Google Scholar
• Xin A, Masson F, Liao Y, Preston S, Guan T, Gloury R, Olshansky M, Lin J-X, Li P, Speed TP. A molecular threshold for effector CD8+ T cell differentiation controlled by transcription factors Blimp-1 and T-bet. Nat Immunol. 2016 Apr;17(4):422–432. doi:10.1038/ni.3410.
   PubMed Web of Science ®Google Scholar
• Shin H, Blackburn SD, Intlekofer AM, Kao C, Angelosanto JM, Reiner SL, Wherry EJ. A Role for the Transcriptional Repressor Blimp-1 in CD8+ T Cell Exhaustion during Chronic Viral Infection. Immunity. 2009 Aug 21;31(2):309–320. doi:10.1016/j.immuni.2009.06.019.
   PubMed Web of Science ®Google Scholar
• Lu P, Youngblood BA, Austin JW, Rasheed Mohammed AU, Butler R, Ahmed R, Boss JM. Blimp-1 represses CD8 T cell expression of PD-1 using a feed-forward transcriptional circuit during acute viral infection. J Exp Med. 2014 Mar 10;211(3):515–527. doi:10.1084/jem.20130208.
   PubMed Web of Science ®Google Scholar
• Wherry EJ. T cell exhaustion. Nat Immunol. 2011 Jun;12(6):492–499. doi:10.1038/ni.2035.
   PubMed Web of Science ®Google Scholar
• Martins GA, Cimmino L, Liao J, Magnusdottir E, Calame K. Blimp-1 directly represses Il2 and the Il2 activator Fos, attenuating T cell proliferation and survival. J Exp Med. 2008 Sep 1;205(9):1959–1965. doi:10.1084/jem.20080526.
   PubMed Web of Science ®Google Scholar
• Crabtree GR, Olson EN. NFAT signaling: choreographing the social lives of cells. Cell. 2002 Apr;109(Suppl):S67–79. doi:10.1016/S0092-8674(02)00699-2.
   PubMed Web of Science ®Google Scholar
• Rao A, Luo C, Hogan PG. Transcription factors of the NFAT family: regulation and function. Annu Rev Immunol. 1997;15:707–747. doi:10.1146/annurev.immunol.15.1.707.
   PubMed Web of Science ®Google Scholar
• Klein-Hessling S, Muhammad K, Klein M, Pusch T, Rudolf R, Flöter J, Qureischi M, Beilhack A, Vaeth M, Kummerow C. NFATc1 controls the cytotoxicity of CD8+ T cells. Nat Commun. 2017 Sep 11;8(1):511. doi:10.1038/s41467-017-00612-6.
   PubMedGoogle Scholar
• Macian F. NFAT proteins: key regulators of T-cell development and function. Nat Rev Immunol. 2005 Jun;5(6):472–484. doi:10.1038/nri1632.
   PubMed Web of Science ®Google Scholar
• Bengsch B, Wherry EJ. The importance of cooperation: partnerless NFAT induces T cell exhaustion. Immunity. 2015 Feb 17;42(2):203–205. doi:10.1016/j.immuni.2015.01.023.
   PubMed Web of Science ®Google Scholar
• Shaw JP, Utz PJ, Durand DB, Toole J, Emmel E, Crabtree G. Identification of a putative regulator of early T cell activation genes. Science. 1988 Jul 8;241(4862):202–205. doi:10.1126/science.3260404.
   PubMed Web of Science ®Google Scholar
• Jain J, McCafffrey PG, Miner Z, Kerppola TK, Lambert JN, Verdine GL, Curran T, Rao A. The T-cell transcription factor NFATp is a substrate for calcineurin and interacts with Fos and Jun. Nature. 1993 Sep 23;365(6444):352–355. doi:10.1038/365352a0.
   PubMed Web of Science ®Google Scholar
• Macian F, Garcia-Rodriguez C, Rao A. Gene expression elicited by NFAT in the presence or absence of cooperative recruitment of Fos and Jun. Embo J. 2000 Sep 1;19(17):4783–4795. doi:10.1093/emboj/19.17.4783.
   PubMed Web of Science ®Google Scholar
• Abe BT, Shin DS, Mocholi E, Macian F. NFAT1 supports tumor-induced anergy of CD4+ T cells. Cancer Res. 2012 Sep 15;72(18):4642–4651. doi:10.1158/0008-5472.CAN-11-3775.
   PubMed Web of Science ®Google Scholar
• Muller MR, Rao A. NFAT, immunity and cancer: a transcription factor comes of age. Nat Rev Immunol. 2010 Sep;10(9):645–656. doi:10.1038/nri2818.
   PubMed Web of Science ®Google Scholar
• Srinivasan M, Frauwirth KA. Reciprocal NFAT1 and NFAT2 nuclear localization in CD8+ anergic T cells is regulated by suboptimal calcium signaling. J Immunol. 2007 Sep 15;179(6):3734–3741. doi:10.4049/jimmunol.179.6.3734.
   PubMed Web of Science ®Google Scholar
• Oestreich KJ, Yoon H, Ahmed R, Boss JM. NFATc1 regulates PD-1 expression upon T cell activation. J Immunol. 2008 Oct 1;181(7):4832–4839. doi:10.4049/jimmunol.181.7.4832.
   PubMed Web of Science ®Google Scholar
• Teixeira LK, Fonseca BP, Vieira-de-Abreu A, Barboza BA, Robbs BK, Bozza PT, Viola JPB. IFN-γ production by CD8+ T cells depends on NFAT1 transcription factor and regulates Th differentiation. J Immunol. 2005 Nov 1;175(9):5931–5939. doi:10.4049/jimmunol.175.9.5931.
   PubMed Web of Science ®Google Scholar
• Agnellini P, Wolint P, Rehr M, Cahenzli J, Karrer U, Oxenius A. Impaired NFAT nuclear translocation results in split exhaustion of virus-specific CD8+ T cell functions during chronic viral infection. Proc Natl Acad Sci U S A. 2007 Mar 13;104(11):4565–4570. doi:10.1073/pnas.0610335104.
   PubMed Web of Science ®Google Scholar
• Quigley M, Pereyra F, Nilsson B, Porichis F, Fonseca C, Eichbaum Q, Julg B, Jesneck JL, Brosnahan K, Imam S. Transcriptional analysis of HIV-specific CD8+ T cells shows that PD-1 inhibits T cell function by upregulating BATF. Nat Med. 2010 Oct;16(10):1147–1151. doi:10.1038/nm.2232.
   PubMed Web of Science ®Google Scholar
• Williams KL, Nanda I, Lyons GE, Kuo C, Schmid M, Leiden J, Kaplan M, Taparowsky E. Characterization of murine BATF: a negative regulator of activator protein-1 activity in the thymus. Eur J Immunol. 2001 May;31(5):1620–1627. doi:10.1002/1521-4141(200105)31:5<1620::AID-IMMU1620>3.0.CO;2-3.
   PubMed Web of Science ®Google Scholar
• Shahinian A, Pfeffer K, Lee KP, Kundig T, Kishihara K, Wakeham A, Kawai K, Ohashi P, Thompson C, Mak T. Differential T cell costimulatory requirements in CD28-deficient mice. Science. 1993 Jul 30;261(5121):609–612. doi:10.1126/science.7688139.
   PubMed Web of Science ®Google Scholar
• Kurachi M, Barnitz RA, Yosef N, Odorizzi PM, DiIorio MA, Lemieux ME, Yates K, Godec J, Klatt MG, Regev A. The transcription factor BATF operates as an essential differentiation checkpoint in early effector CD8+ T cells. Nat Immunol. 2014 Apr;15(4):373–383. doi:10.1038/ni.2834.
   PubMed Web of Science ®Google Scholar
• Hess Michelini R, Doedens AL, Goldrath AW, Hedrick SM. Differentiation of CD8 memory T cells depends on Foxo1. J Exp Med. 2013 Jun 3;210(6):1189–1200. doi:10.1084/jem.20130392.
   PubMed Web of Science ®Google Scholar
• Staron MM, Gray SM, Marshall HD, Parish I, Chen J, Perry C, Cui G, Li M, Kaech S. The transcription factor FoxO1 sustains expression of the inhibitory receptor PD-1 and survival of antiviral CD8+ T cells during chronic infection. Immunity. 2014 Nov 20;41(5):802–814. doi:10.1016/j.immuni.2014.10.013.
   PubMed Web of Science ®Google Scholar
• Delpoux A, Michelini RH, Verma S, Lai C-Y, Omilusik KD, Utzschneider DT, Redwood AJ, Goldrath AW, Benedict CA, Hedrick SM. Continuous activity of Foxo1 is required to prevent anergy and maintain the memory state of CD8+ T cells. J Exp Med. 2018 Feb 5;215(2):575–594. doi:10.1084/jem.20170697.
   PubMed Web of Science ®Google Scholar
• Delpoux A, Lai C-Y, Hedrick SM, Doedens AL. FOXO1 opposition of CD8(+) T cell effector programming confers early memory properties and phenotypic diversity. Proc Natl Acad Sci U S A. 2017 Oct 17;114(42):E8865–E8874. doi:10.1073/pnas.1618916114.
   PubMed Web of Science ®Google Scholar
• Utzschneider DT, Delpoux A, Wieland D, Huang X, Lai C-Y, Hofmann M, Thimme R, Hedrick SM. Active maintenance of T cell memory in acute and chronic viral infection depends on continuous expression of FOXO1. Cell Rep. 2018 Mar 27;22(13):3454–3467. doi:10.1016/j.celrep.2018.03.020.
   PubMed Web of Science ®Google Scholar
• Thomas MJ, Seto E. Unlocking the mechanisms of transcription factor YY1: are chromatin modifying enzymes the key? Gene. 1999 Aug 20;236(2):197–208. doi:10.1016/S0378-1119(99)00261-9.
   PubMed Web of Science ®Google Scholar
• Gordon S, Akopyan G, Garban H, Bonavida B. Transcription factor YY1: structure, function, and therapeutic implications in cancer biology. Oncogene. 2006 Feb 23;25(8):1125–1142. doi:10.1038/sj.onc.1209080.
   PubMed Web of Science ®Google Scholar
• Shi Y, Lee JS, Galvin KM. Everything you have ever wanted to know about Yin Yang 1. Biochim Biophys Acta. 1997 Apr 18;1332(2):F49–66. doi:10.1016/s0304-419x(96)00044-3.
   PubMed Web of Science ®Google Scholar
• Hwang SS, Kim YU, Lee S, Jang SW, Kim MK, Koh BH, Lee W, Kim J, Souabni A, Busslinger M. Transcription factor YY1 is essential for regulation of the Th2 cytokine locus and for Th2 cell differentiation. Proc Natl Acad Sci U S A. 2013 Jan 2;110(1):276–281. doi:10.1073/pnas.1214682110.
   PubMed Web of Science ®Google Scholar
• Yu B, Zhang K, Milner JJ, Toma C, Chen R, Scott-Browne JP, Pereira RM, Crotty S, Chang JT, Pipkin ME. Erratum: epigenetic landscapes reveal transcription factors that regulate CD8+ T cell differentiation. Nat Immunol. 2017 May 18;18(6):705. doi:10.1038/ni0617-705b.
   PubMed Web of Science ®Google Scholar
• Alfei F, Kanev K, Hofmann M, Wu M, Ghoneim HE, Roelli P, Utzschneider DT, von Hoesslin M, Cullen JG, Fan Y. TOX reinforces the phenotype and longevity of exhausted T cells in chronic viral infection. Nature. 2019 Jun 17;571(7764):265–269. doi:10.1038/s41586-019-1326-9.
   PubMed Web of Science ®Google Scholar
• O’Flaherty E, Kaye J. TOX defines a conserved subfamily of HMG-box proteins. BMC Genomics. 2003 Apr 2;4(1):13. doi:10.1186/1471-2164-4-13.
   PubMedGoogle Scholar
• Aliahmad P, Kaye J. Development of all CD4 T lineages requires nuclear factor TOX. J Exp Med. 2008 Jan 21;205(1):245–256. doi:10.1084/jem.20071944.
   PubMed Web of Science ®Google Scholar
• Scott AC, Dundar F, Zumbo P, Chandran SS, Klebanoff CA, Shakiba M, Trivedi P, Menocal L, Appleby H, Camara S. TOX is a critical regulator of tumour-specific T cell differentiation. Nature. 2019 Jun 17;571(7764):270–274. doi:10.1038/s41586-019-1324-y.
   PubMed Web of Science ®Google Scholar
• Shaw LA, Belanger S, Omilusik KD, Cho S, Scott-Browne JP, Nance JP, Goulding J, Lasorella A, Lu L-F, Crotty S. Id2 reinforces TH1 differentiation and inhibits E2A to repress TFH differentiation. Nat Immunol. 2016 Jul;17(7):834–843. doi:10.1038/ni.3461.
   PubMed Web of Science ®Google Scholar
• Latif F, Tory K, Gnarra J, Yao M, Duh F, Orcutt M, Stackhouse T, Kuzmin I, Modi W, Geil L. Identification of the von Hippel-Lindau disease tumor suppressor gene. Science. 1993 May 28;260(5112):1317–1320. doi:10.1126/science.8493574.
   PubMed Web of Science ®Google Scholar
• Doedens AL, Phan AT, Stradner MH, Fujimoto JK, Nguyen JV, Yang E, Johnson RS, Goldrath AW. Hypoxia-inducible factors enhance the effector responses of CD8+ T cells to persistent antigen. Nat Immunol. 2013 Nov;14(11):1173–1182. doi:10.1038/ni.2714.
   PubMed Web of Science ®Google Scholar
• Sen DR, Kaminski J, Barnitz RA, Kurachi M, Gerdemann U, Yates KB, Tsao H-W, Godec J, LaFleur MW, Brown FD. The epigenetic landscape of T cell exhaustion. Science. 2016 Dec 2;354(6316):1165–1169. doi:10.1126/science.aae0491.
   PubMed Web of Science ®Google Scholar
• Scott-Browne JP, Lopez-Moyado IF, Trifari S, Wong V, Chavez L, Rao A, Pereira RM. Dynamic changes in chromatin accessibility occur in CD8 + T cells responding to viral infection. Immunity. 2016 Dec 20;45(6):1327–1340. doi:10.1016/j.immuni.2016.10.028.
   PubMed Web of Science ®Google Scholar
• Alfei F, Zehn D. T cell exhaustion: an epigenetically imprinted phenotypic and functional makeover. Trends Mol Med. 2017 Sep;23(9):769–771. doi:10.1016/j.molmed.2017.07.006.
   PubMed Web of Science ®Google Scholar
• Philip M, Fairchild L, Sun L, Horste EL, Camara S, Shakiba M, Scott AC, Viale A, Lauer P, Merghoub T. Chromatin states define tumour-specific T cell dysfunction and reprogramming. Nature. 2017 May 25;545(7655):452–456. doi:10.1038/nature22367.
   PubMed Web of Science ®Google Scholar
• Doering TA, Crawford A, Angelosanto JM, Paley M, Ziegler C, Wherry E. Network analysis reveals centrally connected genes and pathways involved in CD8+ T cell exhaustion versus memory. Immunity. 2012 Dec 14;37(6):1130–1144. doi:10.1016/j.immuni.2012.08.021.
   PubMed Web of Science ®Google Scholar
• Khan O, Giles JR, McDonald S, Manne S, Ngiow SF, Patel KP, Werner MT, Huang AC, Alexander KA, Wu JE. TOX transcriptionally and epigenetically programs CD8+ T cell exhaustion. Nature. 2019 Jun 17;571(7764):211–218. doi:10.1038/s41586-019-1325-x.
   PubMed Web of Science ®Google Scholar
• Brentjens RJ, Davila ML, Riviere I, Park J, Wang X, Cowell LG, Bartido S, Stefanski J, Taylor C, Olszewska M. CD19-targeted T cells rapidly induce molecular remissions in adults with chemotherapy-refractory acute lymphoblastic leukemia. Sci Transl Med. 2013 Mar 20;5(177):177ra38. doi:10.1126/scitranslmed.3005930.
   PubMed Web of Science ®Google Scholar
• Grupp SA, Kalos M, Barrett D, Aplenc R, Porter DL, Rheingold SR, Teachey DT, Chew A, Hauck B, Wright JF. Chimeric Antigen Receptor–Modified T Cells for Acute Lymphoid Leukemia. N Engl J Med. 2013 Apr 18;368(16):1509–1518. doi:10.1056/NEJMoa1215134.
   PubMed Web of Science ®Google Scholar
• Porter DL, Levine BL, Kalos M, Bagg A, June CH. Chimeric antigen receptor–modified T cells in chronic lymphoid leukemia. N Engl J Med. 2011 Aug 25;365(8):725–733. doi:10.1056/NEJMoa1103849.
   PubMed Web of Science ®Google Scholar
• Junghans RP. The challenges of solid tumor for designer CAR-T therapies: a 25-year perspective. Cancer Gene Ther. 2017 Mar;24(3):89–99. doi:10.1038/cgt.2016.82.
   PubMed Web of Science ®Google Scholar
• Kershaw MH, Westwood JA, Parker LL, Wang G, Eshhar Z, Mavroukakis SA, White DE, Wunderlich JR, Canevari S, Rogers-Freezer L. A phase I study on adoptive immunotherapy using gene-modified T cells for ovarian cancer. Clin Cancer Res. 2006 Oct 15;12(20):6106–6115. doi:10.1158/1078-0432.CCR-06-1183.
   PubMed Web of Science ®Google Scholar
• Lamers CH, Sleijfer S, van Steenbergen S, van Elzakker P, van Krimpen B, Groot C, Vulto A, den Bakker M, Oosterwijk E, Debets R. Treatment of metastatic renal cell carcinoma with CAIX CAR-engineered T cells: clinical evaluation and management of on-target toxicity. Mol Ther. 2013 Apr;21(4):904–912. doi:10.1038/mt.2013.17.
   PubMed Web of Science ®Google Scholar
• Long AH, Haso WM, Shern JF, Wanhainen KM, Murgai M, Ingaramo M, Smith JP, Walker AJ, Kohler ME, Venkateshwara VR. 4-1BB costimulation ameliorates T cell exhaustion induced by tonic signaling of chimeric antigen receptors. Nat Med. 2015 May 4;21(6):581–590. doi:10.1038/nm.3838.
   PubMed Web of Science ®Google Scholar
• Fraietta JA, Lacey SF, Orlando EJ, Pruteanu-Malinici I, Gohil M, Lundh S, Boesteanu AC, Wang Y, O’Connor RS, Hwang W-T. Determinants of response and resistance to CD19 chimeric antigen receptor (CAR) T cell therapy of chronic lymphocytic leukemia. Nat Med. 2018 May;24(5):563–571. doi:10.1038/s41591-018-0010-1.
   PubMed Web of Science ®Google Scholar
• Cherkassky L, Morello A, Villena-Vargas J, Feng Y, Dimitrov DS, Jones DR, Sadelain M, Adusumilli PS. Human CAR T cells with cell-intrinsic PD-1 checkpoint blockade resist tumor-mediated inhibition. J Clin Invest. 2016 Aug 1;126(8):3130–3144. doi:10.1172/JCI83092.
   PubMed Web of Science ®Google Scholar
• John LB, Devaud C, Duong CP, Yong CS, Beavis PA, Haynes NM, Chow MT, Smyth MJ, Kershaw MH, Darcy PK. Anti-PD-1 antibody therapy potently enhances the eradication of established tumors by gene-modified T cells. Clin Cancer Res. 2013 Oct 15;19(20):5636–5646. doi:10.1158/1078-0432.CCR-13-0458.
   PubMed Web of Science ®Google Scholar
• Zolov SN, Rietberg SP, Bonifant CL. Programmed cell death protein 1 activation preferentially inhibits CD28.CAR–T cells. Cytotherapy. 2018 Oct 8;20(10):1259–1266. doi:10.1016/j.jcyt.2018.07.005.
   PubMed Web of Science ®Google Scholar
• Park JR, Digiusto DL, Slovak M, Wright C, Naranjo A, Wagner J, Meechoovet HB, Bautista C, Chang W-C, Ostberg JR. Adoptive transfer of chimeric antigen receptor re-directed cytolytic T lymphocyte clones in patients with neuroblastoma. Mol Ther. 2007 Apr;15(4):825–833. doi:10.1038/sj.mt.6300104.
   PubMed Web of Science ®Google Scholar
• Till BG, Jensen MC, Wang J, Qian X, Gopal AK, Maloney DG, Lindgren CG, Lin Y, Pagel JM, Budde LE. CD20-specific adoptive immunotherapy for lymphoma using a chimeric antigen receptor with both CD28 and 4-1BB domains: pilot clinical trial results. Blood. 2012 Apr 26;119(17):3940–3950. doi:10.1182/blood-2011-10-387969.
   PubMed Web of Science ®Google Scholar
• Emran AA, Chatterjee A, Rodger EJ, Tiffen JC, Gallagher SJ, Eccles MR, Hersey P. Targeting DNA methylation and EZH2 activity to overcome melanoma resistance to immunotherapy. Trends Immunol. 2019 Apr;40(4):328–344. doi:10.1016/j.it.2019.02.004.
   PubMed Web of Science ®Google Scholar
• Salmond RJ, Alexander DR. SHP2 forecast for the immune system: fog gradually clearing. Trends Immunol. 2006 Mar;27(3):154–160. doi:10.1016/j.it.2006.01.007.
   PubMed Web of Science ®Google Scholar
• Hui E, Cheung J, Zhu J, Su X, Taylor MJ, Wallweber HA, Sasmal DK, Huang J, Kim JM, Mellman I. T cell costimulatory receptor CD28 is a primary target for PD-1–mediated inhibition. Science. 2017 Mar 31;355(6332):1428–1433. doi:10.1126/science.aaf1292.
   PubMed Web of Science ®Google Scholar
• Oehen S, Brduscha-Riem K. Differentiation of naive CTL to effector and memory CTL: correlation of effector function with phenotype and cell division. J Immunol. 1998 Nov 15;161(10):5338–5346.
   PubMed Web of Science ®Google Scholar
• Williams MA, Bevan MJ. Effector and memory CTL differentiation. Annu Rev Immunol. 2007;25(1):171–192. doi:10.1146/annurev.immunol.25.022106.141548.
   PubMedGoogle Scholar
• Akondy RS, Fitch M, Edupuganti S, Yang S, Kissick HT, Li KW, Youngblood BA, Abdelsamed HA, McGuire DJ, Cohen KW. Origin and differentiation of human memory CD8 T cells after vaccination. Nature. 2017 Dec 21;552(7685):362–367. doi:10.1038/nature24633.
   PubMed Web of Science ®Google Scholar
• Youngblood B, Hale JS, Kissick HT, Ahn E, Xu X, Wieland A, Araki K, West EE, Ghoneim HE, Fan Y. Effector CD8 T cells dedifferentiate into long-lived memory cells. Nature. 2017 Dec 21;552(7685):404–409. doi:10.1038/nature25144.
   PubMed Web of Science ®Google Scholar
• Pace L, Goudot C, Zueva E, Gueguen P, Burgdorf N, Waterfall JJ, Quivy J-P, Almouzni G, Amigorena S. The epigenetic control of stemness in CD8(+) T cell fate commitment. Science. 2018 Jan 12;359(6372):177–186. doi:10.1126/science.aah6499.
   PubMed Web of Science ®Google Scholar
• Reinhardt RL, Khoruts A, Merica R, Zell T, Jenkins MK. Visualizing the generation of memory CD4 T cells in the whole body. Nature. 2001 Mar 1;410(6824):101–105. doi:10.1038/35065111.
   PubMed Web of Science ®Google Scholar
• Masopust D. Preferential localization of effector memory cells in nonlymphoid tissue. Science. 2001 Mar 23;291(5512):2413–2417. doi:10.1126/science.1058867.
   PubMed Web of Science ®Google Scholar
• Balkhi MY, Ma Q, Ahmad S, Junghans RP. T cell exhaustion and Interleukin 2 downregulation. Cytokine. 2015 Feb;71(2):339–347. doi:10.1016/j.cyto.2014.11.024.
   PubMed Web of Science ®Google Scholar
• Okazaki T, Honjo T. The PD-1-PD-L pathway in immunological tolerance. Trends Immunol. 2006 Apr;27(4):195–201. doi:10.1016/j.it.2006.02.001.
   PubMed Web of Science ®Google Scholar
• Keir ME, Liang SC, Guleria I, Latchman YE, Qipo A, Albacker LA, Koulmanda M, Freeman GJ, Sayegh MH, Sharpe AH. Tissue expression of PD-L1 mediates peripheral T cell tolerance. J Exp Med. 2006 Apr 17;203(4):883–895. doi:10.1084/jem.20051776.
   PubMed Web of Science ®Google Scholar