1932

Abstract

Antigen-specific CD8 T cells are central to the control of chronic infections and cancer, but persistent antigen stimulation results in T cell exhaustion. Exhausted CD8 T cells have decreased effector function and proliferative capacity, partly caused by overexpression of inhibitory receptors such as programmed cell death (PD)-1. Blockade of the PD-1 pathway has opened a new therapeutic avenue for reinvigorating T cell responses, with positive outcomes especially for patients with cancer. Other strategies to restore function in exhausted CD8 T cells are currently under evaluation—many in combination with PD-1-targeted therapy. Exhausted CD8 T cells comprise heterogeneous cell populations with unique differentiation and functional states. A subset of stem cell–like PD-1+ CD8 T cells responsible for the proliferative burst after PD-1 therapy has been recently described. A greater understanding of T cell exhaustion is imperative to establish rational immunotherapeutic interventions.

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2018-01-29
2024-03-29
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Literature Cited

  1. Wherry EJ, Ahmed R. 1.  2004. Memory CD8 T-cell differentiation during viral infection. J. Virol. 78:5535–45 [Google Scholar]
  2. Williams MA, Bevan MJ. 2.  2007. Effector and memory CTL differentiation. Annu. Rev. Immunol. 25:171–92 [Google Scholar]
  3. Gallimore A, Glithero A, Godkin A. 3.  et al. 1998. Induction and exhaustion of lymphocytic choriomeningitis virus–specific cytotoxic T lymphocytes visualized using soluble tetrameric major histocompatibility complex class I–peptide complexes. J. Exp. Med. 187:1383–93 [Google Scholar]
  4. Zajac AJ, Blattman JN, Murali-Krishna K. 4.  et al. 1998. Viral immune evasion due to persistence of activated T cells without effector function. J. Exp. Med. 188:2205–13 [Google Scholar]
  5. Moskophidis D, Lechner F, Pircher H, Zinkernagel RM. 5.  1993. Virus persistence in acutely infected immunocompetent mice by exhaustion of antiviral cytotoxic effector T cells. Nature 362:758–61First description of T cell exhaustion by demonstrating impaired cytotoxic activity during viral persistence. [Google Scholar]
  6. Wherry EJ, Kurachi M. 6.  2015. Molecular and cellular insights into T cell exhaustion. Nat. Rev. Immunol. 15:486–99 [Google Scholar]
  7. Wherry EJ, Ha SJ, Kaech SM. 7.  et al. 2007. Molecular signature of CD8+ T cell exhaustion during chronic viral infection. Immunity 27:670–84First paper describing a molecular signature of exhausted CD8 T cells. [Google Scholar]
  8. Sen DR, Kaminski J, Barnitz RA. 8.  et al. 2016. The epigenetic landscape of T cell exhaustion. Science 354:1165–69Together with Reference 11, first description of epigenetic landscape of exhausted CD8 T cells. [Google Scholar]
  9. Scott-Browne JP, Lopez-Moyado IF, Trifari S. 9.  et al. 2016. Dynamic changes in chromatin accessibility occur in CD8+ T cells responding to viral infection. Immunity 45:1327–40 [Google Scholar]
  10. Scharer CD, Bally AP, Gandham B, Boss JM. 10.  2017. Cutting edge: chromatin accessibility programs CD8 T cell memory. J. Immunol. 198:2238–43 [Google Scholar]
  11. Pauken KE, Sammons MA, Odorizzi PM. 11.  et al. 2016. Epigenetic stability of exhausted T cells limits durability of reinvigoration by PD-1 blockade. Science 354:1160–65 [Google Scholar]
  12. Bengsch B, Johnson AL, Kurachi M. 12.  et al. 2016. Bioenergetic insufficiencies due to metabolic alterations regulated by the inhibitory receptor PD-1 are an early driver of CD8+ T cell exhaustion. Immunity 45:358–73 [Google Scholar]
  13. Barber DL, Wherry EJ, Masopust D. 13.  et al. 2006. Restoring function in exhausted CD8 T cells during chronic viral infection. Nature 439:682–87Pillar article showing the mechanistic basis of T cell exhaustion and efficacy of PD-1 blockade. [Google Scholar]
  14. Mueller SN, Ahmed R. 14.  2009. High antigen levels are the cause of T cell exhaustion during chronic viral infection. PNAS 106:8623–28 [Google Scholar]
  15. Day CL, Kaufmann DE, Kiepiela P. 15.  et al. 2006. PD-1 expression on HIV-specific T cells is associated with T-cell exhaustion and disease progression. Nature 443:350–54First study showing PD-1 is a major regulator of T cell exhaustion in humans. [Google Scholar]
  16. Baitsch L, Baumgaertner P, Devevre E. 16.  et al. 2011. Exhaustion of tumor-specific CD8+ T cells in metastases from melanoma patients. J. Clin. Investig. 121:2350–60 [Google Scholar]
  17. Freeman GJ, Long AJ, Iwai Y. 17.  et al. 2000. Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation. J. Exp. Med. 192:1027–34 [Google Scholar]
  18. Dong H, Strome SE, Salomao DR. 18.  et al. 2002. Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion. Nat. Med. 8:793–800 [Google Scholar]
  19. Iwai Y, Ishida M, Tanaka Y. 19.  et al. 2002. Involvement of PD-L1 on tumor cells in the escape from host immune system and tumor immunotherapy by PD-L1 blockade. PNAS 99:12293–97 [Google Scholar]
  20. Im SJ, Hashimoto M, Gerner MY. 20.  et al. 2016. Defining CD8+ T cells that provide the proliferative burst after PD-1 therapy. Nature 537:417–21Together with References 101 and 100, this study defines cell populations responding to PD-1 therapy. [Google Scholar]
  21. Johnston RJ, Comps-Agrar L, Hackney J. 21.  et al. 2014. The immunoreceptor TIGIT regulates antitumor and antiviral CD8+ T cell effector function. Cancer Cell 26:923–37 [Google Scholar]
  22. Blackburn SD, Shin H, Haining WN. 22.  et al. 2009. Coregulation of CD8+ T cell exhaustion by multiple inhibitory receptors during chronic viral infection. Nat. Immunol. 10:29–37 [Google Scholar]
  23. Jin HT, Anderson AC, Tan WG. 23.  et al. 2010. Cooperation of Tim-3 and PD-1 in CD8 T-cell exhaustion during chronic viral infection. PNAS 107:14733–38 [Google Scholar]
  24. Sakuishi K, Apetoh L, Sullivan JM. 24.  et al. 2010. Targeting Tim-3 and PD-1 pathways to reverse T cell exhaustion and restore anti-tumor immunity. J. Exp. Med. 207:2187–94 [Google Scholar]
  25. Thommen DS, Schreiner J, Muller P. 25.  et al. 2015. Progression of lung cancer is associated with increased dysfunction of T cells defined by coexpression of multiple inhibitory receptors. Cancer Immunol. Res. 3:1344–55 [Google Scholar]
  26. Gros A, Robbins PF, Yao X. 26.  et al. 2014. PD-1 identifies the patient-specific CD8+ tumor-reactive repertoire infiltrating human tumors. J. Clin. Investig. 124:2246–59 [Google Scholar]
  27. Schildberg FA, Klein SR, Freeman GJ, Sharpe AH. 27.  2016. Coinhibitory pathways in the B7-CD28 ligand-receptor family. Immunity 44:955–72 [Google Scholar]
  28. Yokosuka T, Takamatsu M, Kobayashi-Imanishi W. 28.  et al. 2012. Programmed cell death 1 forms negative costimulatory microclusters that directly inhibit T cell receptor signaling by recruiting phosphatase SHP2. J. Exp. Med. 209:1201–17 [Google Scholar]
  29. Hui E, Cheung J, Zhu J. 29.  et al. 2017. T cell costimulatory receptor CD28 is a primary target for PD-1-mediated inhibition. Science 355:1428–33 [Google Scholar]
  30. Tumeh PC, Harview CL, Yearley JH. 30.  et al. 2014. PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature 515:568–71 [Google Scholar]
  31. Taube JM, Klein A, Brahmer JR. 31.  et al. 2014. Association of PD-1, PD-1 ligands, and other features of the tumor immune microenvironment with response to anti-PD-1 therapy. Clin. Cancer Res. 20:5064–74 [Google Scholar]
  32. Youngblood B, Noto A, Porichis F. 32.  et al. 2013. Cutting edge: prolonged exposure to HIV reinforces a poised epigenetic program for PD-1 expression in virus-specific CD8 T cells. J. Immunol. 191:540–44 [Google Scholar]
  33. Youngblood B, Oestreich KJ, Ha SJ. 33.  et al. 2011. Chronic virus infection enforces demethylation of the locus that encodes PD-1 in antigen-specific CD8+ T cells. Immunity 35:400–12 [Google Scholar]
  34. Chang CH, Qiu J, O'Sullivan D. 34.  et al. 2015. Metabolic competition in the tumor microenvironment is a driver of cancer progression. Cell 162:1229–41 [Google Scholar]
  35. Staron MM, Gray SM, Marshall HD. 35.  et al. 2014. The transcription factor FoxO1 sustains expression of the inhibitory receptor PD-1 and survival of antiviral CD8+ T cells during chronic infection. Immunity 41:802–14 [Google Scholar]
  36. Patsoukis N, Bardhan K, Chatterjee P. 36.  et al. 2015. PD-1 alters T-cell metabolic reprogramming by inhibiting glycolysis and promoting lipolysis and fatty acid oxidation. Nat. Commun. 6:6692 [Google Scholar]
  37. Velu V, Titanji K, Zhu B. 37.  et al. 2009. Enhancing SIV-specific immunity in vivo by PD-1 blockade. Nature 458:206–10 [Google Scholar]
  38. Fuller MJ, Callendret B, Zhu B. 38.  et al. 2013. Immunotherapy of chronic hepatitis C virus infection with antibodies against programmed cell death-1 (PD-1). PNAS 110:15001–6 [Google Scholar]
  39. Brahmer JR, Tykodi SS, Chow LQ. 39.  et al. 2012. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N. Engl. J. Med. 366:2455–6539 and 40. Sentinel phase I trial showing safety and activity of PD-1 immunotherapy. [Google Scholar]
  40. Topalian SL, Hodi FS, Brahmer JR. 40.  et al. 2012. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N. Engl. J. Med. 366:2443–5439 and 40. Sentinel phase I trial showing safety and activity of PD-1 immunotherapy. [Google Scholar]
  41. Tran E, Robbins PF, Rosenberg SA. 41.  2017. ‘Final common pathway’ of human cancer immunotherapy: targeting random somatic mutations. Nat. Immunol. 18:255–62 [Google Scholar]
  42. Ferris RL, Blumenschein G Jr., Fayette J. 42.  et al. 2016. Nivolumab for recurrent squamous-cell carcinoma of the head and neck. N. Engl. J. Med. 375:1856–67 [Google Scholar]
  43. Nghiem PT, Bhatia S, Lipson EJ. 43.  et al. 2016. PD-1 blockade with pembrolizumab in advanced Merkel-cell carcinoma. N. Engl. J. Med. 374:2542–52 [Google Scholar]
  44. Kaufman HL, Russell J, Hamid O. 44.  et al. 2016. Avelumab in patients with chemotherapy-refractory metastatic Merkel cell carcinoma: a multicentre, single-group, open-label, phase 2 trial. Lancet Oncol 17:1374–85 [Google Scholar]
  45. Wong SQ, Waldeck K, Vergara IA. 45.  et al. 2015. UV-associated mutations underlie the etiology of MCV-negative Merkel cell carcinomas. Cancer Res 75:5228–34 [Google Scholar]
  46. Gardiner D, Lalezari J, Lawitz E. 46.  et al. 2013. A randomized, double-blind, placebo-controlled assessment of BMS-936558, a fully human monoclonal antibody to programmed death-1 (PD-1), in patients with chronic hepatitis C virus infection. PLOS ONE 8:e63818 [Google Scholar]
  47. Gay CL, Bosch RJ, Ritz J. 47.  et al. 2017. Clinical trial of the anti-PD-L1 antibody BMS-936559 in HIV-1 infected participants on suppressive antiretroviral therapy. J. Infect. Dis. 215:1725–33 [Google Scholar]
  48. Robert C, Thomas L, Bondarenko I. 48.  et al. 2011. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N. Engl. J. Med. 364:2517–26 [Google Scholar]
  49. Hodi FS, O'Day SJ, McDermott DF. 49.  et al. 2010. Improved survival with ipilimumab in patients with metastatic melanoma. N. Engl. J. Med. 363:711–23First phase III study demonstrating an overall survival benefit of CTLA-4 immunotherapy in metastatic melanoma. [Google Scholar]
  50. Larkin J, Chiarion-Sileni V, Gonzalez R. 50.  et al. 2015. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N. Engl. J. Med. 373:23–34 [Google Scholar]
  51. Robert C, Schachter J, Long GV. 51.  et al. 2015. Pembrolizumab versus ipilimumab in advanced melanoma. N. Engl. J. Med. 372:2521–32 [Google Scholar]
  52. Wolchok JD, Chiarion-Sileni V, Gonzalez R. 52.  et al. 2017. Overall survival with combined nivolumab and ipilimumab in advanced melanoma. N. Engl. J. Med. 377:1345–56 [Google Scholar]
  53. Pentcheva-Hoang T, Corse E, Allison JP. 53.  2009. Negative regulators of T-cell activation: potential targets for therapeutic intervention in cancer, autoimmune disease, and persistent infections. Immunol. Rev. 229:67–87 [Google Scholar]
  54. Nakamoto N, Cho H, Shaked A. 54.  et al. 2009. Synergistic reversal of intrahepatic HCV-specific CD8 T cell exhaustion by combined PD-1/CTLA-4 blockade. PLOS Pathog 5:e1000313 [Google Scholar]
  55. Bulliard Y, Jolicoeur R, Windman M. 55.  et al. 2013. Activating Fc gamma receptors contribute to the antitumor activities of immunoregulatory receptor-targeting antibodies. J. Exp. Med. 210:1685–93 [Google Scholar]
  56. Simpson TR, Li F, Montalvo-Ortiz W. 56.  et al. 2013. Fc-dependent depletion of tumor-infiltrating regulatory T cells co-defines the efficacy of anti-CTLA-4 therapy against melanoma. J. Exp. Med. 210:1695–710 [Google Scholar]
  57. Selby MJ, Engelhardt JJ, Quigley M. 57.  et al. 2013. Anti-CTLA-4 antibodies of IgG2a isotype enhance antitumor activity through reduction of intratumoral regulatory T cells. Cancer Immunol. Res. 1:32–42 [Google Scholar]
  58. Kaufmann DE, Walker BD. 58.  2009. PD-1 and CTLA-4 inhibitory cosignaling pathways in HIV infection and the potential for therapeutic intervention. J. Immunol. 182:5891–97 [Google Scholar]
  59. Anderson AC, Joller N, Kuchroo VK. 59.  2016. Lag-3, Tim-3, and TIGIT: co-inhibitory receptors with specialized functions in immune regulation. Immunity 44:989–1004 [Google Scholar]
  60. Chen DS, Mellman I. 60.  2013. Oncology meets immunology: the cancer-immunity cycle. Immunity 39:1–10 [Google Scholar]
  61. Walker LSK. 61.  2017. PD-1 and CTLA4: Two checkpoints, one pathway?. Sci. Immunol. 2:eaan3864 [Google Scholar]
  62. Esensten JH, Helou YA, Chopra G. 62.  et al. 2016. CD28 Costimulation: from mechanism to therapy. Immunity 44:973–88 [Google Scholar]
  63. Frauwirth KA, Riley JL, Harris MH. 63.  et al. 2002. The CD28 signaling pathway regulates glucose metabolism. Immunity 16:769–77 [Google Scholar]
  64. Kamphorst AO, Wieland A, Nasti T. 64.  et al. 2017. Rescue of exhausted CD8 T cells by PD-1-targeted therapies is CD28-dependent. Science 355:1423–27 [Google Scholar]
  65. Noguchi T, Ward JP, Gubin MM. 65.  et al. 2017. Temporally distinct PD-L1 expression by tumor and host cells contributes to immune escape. Cancer Immunol. Res. 5:106–17 [Google Scholar]
  66. Lau J, Cheung J, Navarro A. 66.  et al. 2017. Tumour and host cell PD-L1 is required to mediate suppression of anti-tumour immunity in mice. Nat. Commun. 8:14572 [Google Scholar]
  67. Mikami N, Sakaguchi S. 67.  2014. CD28 signals the differential control of regulatory T cells and effector T cells. Eur. J. Immunol. 44:955–57 [Google Scholar]
  68. Ward-Kavanagh LK, Lin WW, Sedy JR, Ware CF. 68.  2016. The TNF receptor superfamily in co-stimulating and co-inhibitory responses. Immunity 44:1005–19 [Google Scholar]
  69. Bullock TN. 69.  2017. Stimulating CD27 to quantitatively and qualitatively shape adaptive immunity to cancer. Curr. Opin. Immunol. 45:82–88 [Google Scholar]
  70. Salmon H, Idoyaga J, Rahman A. 70.  et al. 2016. Expansion and activation of CD103+ dendritic cell progenitors at the tumor site enhances tumor responses to therapeutic PD-L1 and BRAF inhibition. Immunity 44:924–38 [Google Scholar]
  71. Shin H, Blackburn SD, Blattman JN, Wherry EJ. 71.  2007. Viral antigen and extensive division maintain virus-specific CD8 T cells during chronic infection. J. Exp. Med. 204:941–49 [Google Scholar]
  72. Wherry EJ, Barber DL, Kaech SM. 72.  et al. 2004. Antigen-independent memory CD8 T cells do not develop during chronic viral infection. PNAS 101:16004–9 [Google Scholar]
  73. Ingram JT, Yi JS, Zajac AJ. 73.  2011. Exhausted CD8 T cells downregulate the IL-18 receptor and become unresponsive to inflammatory cytokines and bacterial co-infections. PLOS Pathog 7:e1002273 [Google Scholar]
  74. Elsaesser H, Sauer K, Brooks DG. 74.  2009. IL-21 is required to control chronic viral infection. Science 324:1569–72 [Google Scholar]
  75. Frohlich A, Kisielow J, Schmitz I. 75.  et al. 2009. IL-21R on T cells is critical for sustained functionality and control of chronic viral infection. Science 324:1576–80 [Google Scholar]
  76. Yi JS, Du M, Zajac AJ. 76.  2009. A vital role for interleukin-21 in the control of a chronic viral infection. Science 324:1572–76 [Google Scholar]
  77. Jiang T, Zhou C, Ren S. 77.  2016. Role of IL-2 in cancer immunotherapy. Oncoimmunology 5:e1163462 [Google Scholar]
  78. Blattman JN, Grayson JM, Wherry EJ. 78.  et al. 2003. Therapeutic use of IL-2 to enhance antiviral T-cell responses in vivo. Nat. Med. 9:540–47 [Google Scholar]
  79. Nanjappa SG, Kim EH, Suresh M. 79.  2011. Immunotherapeutic effects of IL-7 during a chronic viral infection in mice. Blood 117:5123–32 [Google Scholar]
  80. Pellegrini M, Calzascia T, Toe JG. 80.  et al. 2011. IL-7 engages multiple mechanisms to overcome chronic viral infection and limit organ pathology. Cell 144:601–13 [Google Scholar]
  81. Fry TJ, Moniuszko M, Creekmore S. 81.  et al. 2003. IL-7 therapy dramatically alters peripheral T-cell homeostasis in normal and SIV-infected nonhuman primates. Blood 101:2294–99 [Google Scholar]
  82. Nugeyre MT, Monceaux V, Beq S. 82.  et al. 2003. IL-7 stimulates T cell renewal without increasing viral replication in simian immunodeficiency virus-infected macaques. J. Immunol. 171:4447–53 [Google Scholar]
  83. Levy Y, Lacabaratz C, Weiss L. 83.  et al. 2009. Enhanced T cell recovery in HIV-1-infected adults through IL-7 treatment. J. Clin. Investig. 119:997–1007 [Google Scholar]
  84. Kovacs JA, Vogel S, Albert JM. 84.  et al. 1996. Controlled trial of interleukin-2 infusions in patients infected with the human immunodeficiency virus. N. Engl. J. Med. 335:1350–56 [Google Scholar]
  85. Mueller YM, Do DH, Altork SR. 85.  et al. 2008. IL-15 treatment during acute simian immunodeficiency virus (SIV) infection increases viral set point and accelerates disease progression despite the induction of stronger SIV-specific CD8+ T cell responses. J. Immunol. 180:350–60 [Google Scholar]
  86. Mueller YM, Petrovas C, Bojczuk PM. 86.  et al. 2005. Interleukin-15 increases effector memory CD8+ T cells and NK cells in simian immunodeficiency virus-infected macaques. J. Virol. 79:4877–85 [Google Scholar]
  87. Brooks DG, Trifilo MJ, Edelmann KH. 87.  et al. 2006. Interleukin-10 determines viral clearance or persistence in vivo. Nat. Med. 12:1301–9 [Google Scholar]
  88. Ejrnaes M, Filippi CM, Martinic MM. 88.  et al. 2006. Resolution of a chronic viral infection after interleukin-10 receptor blockade. J. Exp. Med. 203:2461–72 [Google Scholar]
  89. Naing A, Papadopoulos KP, Autio KA. 89.  et al. 2016. Safety, antitumor activity, and immune activation of pegylated recombinant human interleukin-10 (AM0010) in patients with advanced solid tumors. J. Clin. Oncol. 34:3562–69 [Google Scholar]
  90. Sun Z, Fourcade J, Pagliano O. 90.  et al. 2015. IL10 and PD-1 cooperate to limit the activity of tumor-specific CD8+ T cells. Cancer Res 75:1635–44 [Google Scholar]
  91. West EE, Jin HT, Rasheed AU. 91.  et al. 2013. PD-L1 blockade synergizes with IL-2 therapy in reinvigorating exhausted T cells. J. Clin. Investig. 123:2604–15 [Google Scholar]
  92. Moynihan KD, Opel CF, Szeto GL. 92.  et al. 2016. Eradication of large established tumors in mice by combination immunotherapy that engages innate and adaptive immune responses. Nat. Med. 22:1402–10 [Google Scholar]
  93. Brooks DG, Ha SJ, Elsaesser H. 93.  et al. 2008. IL-10 and PD-L1 operate through distinct pathways to suppress T-cell activity during persistent viral infection. PNAS 105:20428–33 [Google Scholar]
  94. Philip M, Fairchild L, Sun L. 94.  et al. 2017. Chromatin states define tumour-specific T cell dysfunction and reprogramming. Nature 545:452–56 [Google Scholar]
  95. Mognol GP, Spreafico R, Wong V. 95.  et al. 2017. Exhaustion-associated regulatory regions in CD8+ tumor-infiltrating T cells. PNAS 114:E2776–E2785 [Google Scholar]
  96. Schietinger A, Delrow JJ, Basom RS. 96.  et al. 2012. Rescued tolerant CD8 T cells are preprogrammed to reestablish the tolerant state. Science 335:723–27 [Google Scholar]
  97. Chen BF, Chan WY. 97.  2014. The de novo DNA methyltransferase DNMT3A in development and cancer. Epigenetics 9:669–77 [Google Scholar]
  98. Ghoneim HE, Fan Y, Moustaki A. 98.  et al. 2017. De novo epigenetic programs inhibit PD-1 blockade-mediated T cell rejuvenation. Cell 170:142–57 [Google Scholar]
  99. Jones PA, Issa JP, Baylin S. 99.  2016. Targeting the cancer epigenome for therapy. Nat. Rev. Genet. 17:630–41 [Google Scholar]
  100. He R, Hou S, Liu C. 100.  et al. 2016. Follicular CXCR5-expressing CD8+ T cells curtail chronic viral infection. Nature 537:412–28 [Google Scholar]
  101. Utzschneider DT, Charmoy M, Chennupati V. 101.  et al. 2016. T cell factor 1-expressing memory-like CD8+ T cells sustain the immune response to chronic viral infections. Immunity 45:415–27 [Google Scholar]
  102. Wu T, Ji Y, Moseman EA. 102.  et al. 2016. The TCF1-Bcl6 axis counteracts type I interferon to repress exhaustion and maintain T cell stemness. Sci. Immunol. 1:eaai8593 [Google Scholar]
  103. Mueller SN, Vanguri VK, Ha SJ. 103.  et al. 2010. PD-L1 has distinct functions in hematopoietic and nonhematopoietic cells in regulating T cell responses during chronic infection in mice. J. Clin. Investig. 120:2508–15 [Google Scholar]
  104. Jiang H, Li L, Han J. 104.  et al. 2017. CXCR5+ CD8+ T cells indirectly offer B cell help and are inversely correlated with viral load in chronic hepatitis B infection. DNA Cell Biol. 36:321–27 [Google Scholar]
  105. Leong YA, Chen Y, Ong HS. 105.  et al. 2016. CXCR5+ follicular cytotoxic T cells control viral infection in B cell follicles. Nat. Immunol. 17:1187–96 [Google Scholar]
  106. Miles B, Miller SM, Folkvord JM. 106.  et al. 2016. Follicular regulatory CD8 T cells impair the germinal center response in SIV and ex vivo HIV infection. PLoS Pathog 12:e1005924 [Google Scholar]
  107. Mylvaganam GH, Rios D, Abdelaal HM. 107.  et al. 2017. Dynamics of SIV-specific CXCR5+ CD8 T cells during chronic SIV infection. PNAS 114:1976–81 [Google Scholar]
  108. Petrovas C, Ferrando-Martinez S, Gerner MY. 108.  et al. 2017. Follicular CD8 T cells accumulate in HIV infection and can kill infected cells in vitro via bispecific antibodies. Sci. Transl. Med. 9:eaag2285 [Google Scholar]
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