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Abstract

Exhausted CD8 T (Tex) cells are a distinct cell lineage that arise during chronic infections and cancers in animal models and humans. Tex cells are characterized by progressive loss of effector functions, high and sustained inhibitory receptor expression, metabolic dysregulation, poor memory recall and homeostatic self-renewal, and distinct transcriptional and epigenetic programs. The ability to reinvigorate Tex cells through inhibitory receptor blockade, such as αPD-1, highlights the therapeutic potential of targeting this population. Emerging insights into the mechanisms of exhaustion are informing immunotherapies for cancer and chronic infections. However, like other immune cells, Tex cells are heterogeneous and include progenitor and terminal subsets with unique characteristics and responses to checkpoint blockade. Here, we review our current understanding of Tex cell biology, including the developmental paths, transcriptional and epigenetic features, and cell intrinsic and extrinsic factors contributing to exhaustion and how this knowledge may inform therapeutic targeting of Tex cells in chronic infections, autoimmunity, and cancer.

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2019-04-26
2024-05-20
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Literature Cited

  1. 1.
    Sterzl J, Silverstein AM 1967. Developmental aspects of immunity. Adv. Immunol. 6:337–459
    [Google Scholar]
  2. 2.
    Byers VS, Sercarz EE 1968. The X-Y-Z scheme of immunocyte maturation. IV. The exhaustion of memory cells. J. Exp. Med. 127:307–25
    [Google Scholar]
  3. 3.
    Moskophidis D, Lechner F, Pircher H, Zinkernagel RM 1993. Virus persistence in acutely infected immunocompetent mice by exhaustion of antiviral cytotoxic effector T cells. Nature 362:758–61
    [Google Scholar]
  4. 4.
    Zajac AJ, Blattman JN, Murali-Krishna K, Sourdive DJ, Suresh M 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. 5.
    Gallimore A, Glithero A, Godkin A, Tissot AC, Pluckthun A 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]
  6. 6.
    Cui W, Kaech SM 2012. Generation of effector CD8+ T cells and their conversion to memory T cells. Immunol. Rev. 236:151–66
    [Google Scholar]
  7. 7.
    Wherry EJ 2011. T cell exhaustion. Nat. Immunol. 12:492–99
    [Google Scholar]
  8. 8.
    Doering TA, Crawford A, Angelosanto JM, Paley MA, Ziegler CG, Wherry EJ 2012. Network analysis reveals centrally connected genes and pathways involved in CD8+ T cell exhaustion versus memory. Immunity 37:1130–44
    [Google Scholar]
  9. 9.
    Schietinger A, Greenberg PD 2014. Tolerance and exhaustion: defining mechanisms of T cell dysfunction. Trends Immunol 35:51–60
    [Google Scholar]
  10. 10.
    Ahmed R, Salmi A, Butler LD, Chiller JM, Oldstone MB 1984. Selection of genetic variants of lymphocytic choriomeningitis virus in spleens of persistently infected mice. Role in suppression of cytotoxic T lymphocyte response and viral persistence. J. Exp. Med. 160:521–40
    [Google Scholar]
  11. 11.
    Zinkernagel RM 2002. Lymphocytic choriomeningitis virus and immunology. Curr. Top. Microbiol. Immunol. 263:1–5
    [Google Scholar]
  12. 12.
    Goepfert PA, Bansal A, Edwards BH, Ritter GD Jr, Tellez I et al. 2000. A significant number of human immunodeficiency virus epitope-specific cytotoxic T lymphocytes detected by tetramer binding do not produce gamma interferon. J. Virol. 74:10249–55
    [Google Scholar]
  13. 13.
    Shankar P, Russo M, Harnisch B, Patterson M, Skolnik P, Lieberman J 2000. Impaired function of circulating HIV-specific CD8+ T cells in chronic human immunodeficiency virus infection. Blood 96:3094–101
    [Google Scholar]
  14. 14.
    Kostense S, Ogg GS, Manting EH, Gillespie G, Joling J et al. 2001. High viral burden in the presence of major HIV-specific CD8+ T cell expansions: evidence for impaired CTL effector function. Eur. J. Immunol. 31:677–86
    [Google Scholar]
  15. 15.
    Day CL, Kaufmann DE, Kiepiela P, Brown JA, Moodley ES et al. 2006. PD-1 expression on HIV-specific T cells is associated with T-cell exhaustion and disease progression. Nature 443:350–54
    [Google Scholar]
  16. 16.
    Lechner F, Wong DK, Dunbar PR, Chapman R, Chung RT et al. 2000. Analysis of successful immune responses in persons infected with hepatitis C virus. J. Exp. Med. 191:1499–512
    [Google Scholar]
  17. 17.
    Gruener NH, Lechner F, Jung MC, Diepolder H, Gerlach T et al. 2001. Sustained dysfunction of antiviral CD8+ T lymphocytes after infection with hepatitis C virus. J. Virol. 75:5550–58
    [Google Scholar]
  18. 18.
    Ye B, Liu X, Li X, Kong H, Tian L, Chen Y 2015. T-cell exhaustion in chronic hepatitis B infection: current knowledge and clinical significance. Cell Death Dis 6:e1694
    [Google Scholar]
  19. 19.
    Wherry EJ, Kurachi M 2015. Molecular and cellular insights into T cell exhaustion. Nat. Rev. Immunol. 15:486–99
    [Google Scholar]
  20. 20.
    Sharpe AH, Wherry EJ, Ahmed R, Freeman GJ 2007. The function of programmed cell death 1 and its ligands in regulating autoimmunity and infection. Nat. Immunol. 8:239–45
    [Google Scholar]
  21. 21.
    McKinney EF, Lee JC, Jayne DR, Lyons PA, Smith KG 2015. T-cell exhaustion, co-stimulation and clinical outcome in autoimmunity and infection. Nature 523:612–16
    [Google Scholar]
  22. 22.
    Pauken KE, Wherry EJ 2015. Overcoming T cell exhaustion in infection and cancer. Trends Immunol 36:265–76
    [Google Scholar]
  23. 23.
    Zarour HM 2016. Reversing T-cell dysfunction and exhaustion in cancer. Clin. Cancer Res. 22:1856–64
    [Google Scholar]
  24. 24.
    Mumprecht S, Schurch C, Schwaller J, Solenthaler M, Ochsenbein AF 2009. Programmed death 1 signaling on chronic myeloid leukemia-specific T cells results in T-cell exhaustion and disease progression. Blood 114:1528–36
    [Google Scholar]
  25. 25.
    Schietinger A, Philip M, Krisnawan VE, Chiu EY, Delrow JJ et al. 2016. Tumor-specific T cell dysfunction is a dynamic antigen-driven differentiation program initiated early during tumorigenesis. Immunity 45:389–401
    [Google Scholar]
  26. 26.
    Huang AC, Postow MA, Orlowski RJ, Mick R, Bengsch B et al. 2017. T-cell invigoration to tumour burden ratio associated with anti-PD-1 response. Nature 545:60–65
    [Google Scholar]
  27. 27.
    Baitsch L, Baumgaertner P, Devevre E, Raghav SK, Legat A et al. 2011. Exhaustion of tumor-specific CD8+ T cells in metastases from melanoma patients. J. Clin. Investig. 121:2350–60
    [Google Scholar]
  28. 28.
    Lee PP, Yee C, Savage PA, Fong L, Brockstedt D et al. 1999. Characterization of circulating T cells specific for tumor-associated antigens in melanoma patients. Nat. Med. 5:677–85
    [Google Scholar]
  29. 29.
    Ahmadzadeh M, Johnson LA, Heemskerk B, Wunderlich JR, Dudley ME et al. 2009. Tumor antigen-specific CD8 T cells infiltrating the tumor express high levels of PD-1 and are functionally impaired. Blood 114:1537–44
    [Google Scholar]
  30. 30.
    Fourcade J, Sun Z, Benallaoua M, Guillaume P, Luescher IF et al. 2010. Upregulation of Tim-3 and PD-1 expression is associated with tumor antigen-specific CD8+ T cell dysfunction in melanoma patients. J. Exp. Med. 207:2175–86
    [Google Scholar]
  31. 31.
    Matsuzaki J, Gnjatic S, Mhawech-Fauceglia P, Beck A, Miller A et al. 2010. Tumor-infiltrating NY-ESO-1-specific CD8+ T cells are negatively regulated by LAG-3 and PD-1 in human ovarian cancer. PNAS 107:7875–80
    [Google Scholar]
  32. 32.
    Zhang Y, Huang S, Gong D, Qin Y, Shen Q 2010. Programmed death-1 upregulation is correlated with dysfunction of tumor-infiltrating CD8+ T lymphocytes in human non-small cell lung cancer. Cell Mol. Immunol. 7:389–95
    [Google Scholar]
  33. 33.
    Bengsch B, Ohtani T, Herati RS, Bovenschen N, Chang KM, Wherry EJ 2018. Deep immune profiling by mass cytometry links human T and NK cell differentiation and cytotoxic molecule expression patterns. J. Immunol. Methods 453:3–10
    [Google Scholar]
  34. 34.
    Gandhi MK, Lambley E, Duraiswamy J, Dua U, Smith C et al. 2006. Expression of LAG-3 by tumor-infiltrating lymphocytes is coincident with the suppression of latent membrane antigen-specific CD8+ T-cell function in Hodgkin lymphoma patients. Blood 108:2280–89
    [Google Scholar]
  35. 35.
    Riches JC, Davies JK, McClanahan F, Fatah R, Iqbal S et al. 2013. T cells from CLL patients exhibit features of T-cell exhaustion but retain capacity for cytokine production. Blood 121:1612–21
    [Google Scholar]
  36. 36.
    Fraietta JA, Lacey SF, Orlando EJ, Pruteanu-Malinici I, Gohil M et al. 2018. Determinants of response and resistance to CD19 chimeric antigen receptor (CAR) T cell therapy of chronic lymphocytic leukemia. Nat. Med. 24:563–71
    [Google Scholar]
  37. 37.
    Kim PS, Ahmed R 2010. Features of responding T cells in cancer and chronic infection. Curr. Opin. Immunol. 22:223–30
    [Google Scholar]
  38. 38.
    Gros A, Robbins PF, Yao X, Li YF, Turcotte S et al. 2014. PD-1 identifies the patient-specific CD8+ tumor-reactive repertoire infiltrating human tumors. J. Clin. Investig. 124:2246–59
    [Google Scholar]
  39. 39.
    Zenz T 2013. Exhausting T cells in CLL. Blood 121:1485–86
    [Google Scholar]
  40. 40.
    Fourcade J, Kudela P, Sun Z, Shen H, Land SR et al. 2009. PD-1 is a regulator of NY-ESO-1-specific CD8+ T cell expansion in melanoma patients. J. Immunol. 182:5240–49
    [Google Scholar]
  41. 41.
    Radoja S, Saio M, Schaer D, Koneru M, Vukmanovic S, Frey AB 2001. CD8+ tumor-infiltrating T cells are deficient in perforin-mediated cytolytic activity due to defective microtubule-organizing center mobilization and lytic granule exocytosis. J. Immunol. 167:5042–51
    [Google Scholar]
  42. 42.
    Pauken KE, Sammons MA, Odorizzi PM, Manne S, Godec J et al. 2016. Epigenetic stability of exhausted T cells limits durability of reinvigoration by PD-1 blockade. Science 354:1160–65
    [Google Scholar]
  43. 43.
    Sen DR, Kaminski J, Barnitz RA, Kurachi M, Gerdemann U et al. 2016. The epigenetic landscape of T cell exhaustion. Science 354:1165–69
    [Google Scholar]
  44. 44.
    Philip M, Fairchild L, Sun L, Horste EL, Camara S et al. 2017. Chromatin states define tumour-specific T cell dysfunction and reprogramming. Nature 545:452–56
    [Google Scholar]
  45. 45.
    Barber DL, Wherry EJ, Masopust D, Zhu B, Allison JP et al. 2006. Restoring function in exhausted CD8 T cells during chronic viral infection. Nature 439:682–87
    [Google Scholar]
  46. 46.
    Kahan SM, Wherry EJ, Zajac AJ 2015. T cell exhaustion during persistent viral infections. Virology 479–480:180–93
    [Google Scholar]
  47. 47.
    Iwai H, Masaoka N, Ishii T, Satoh S 2002. A pectin glucuronyltransferase gene is essential for intercellular attachment in the plant meristem. PNAS 99:16319–24
    [Google Scholar]
  48. 48.
    Hirano F, Kaneko K, Tamura H, Dong H, Wang S et al. 2005. Blockade of B7-H1 and PD-1 by monoclonal antibodies potentiates cancer therapeutic immunity. Cancer Res 65:1089–96
    [Google Scholar]
  49. 49.
    Keir ME, Butte MJ, Freeman GJ, Sharpe AH 2008. PD-1 and its ligands in tolerance and immunity. Annu. Rev. Immunol. 26:677–704
    [Google Scholar]
  50. 50.
    Curiel TJ, Wei S, Dong H, Alvarez X, Cheng P et al. 2003. Blockade of B7-H1 improves myeloid dendritic cell-mediated antitumor immunity. Nat. Med. 9:562–67
    [Google Scholar]
  51. 51.
    Topalian SL, Drake CG, Pardoll DM 2012. Targeting the PD-1/B7-H1(PD-L1) pathway to activate anti-tumor immunity. Curr. Opin. Immunol. 24:207–12
    [Google Scholar]
  52. 52.
    Iwai Y, Terawaki S, Honjo T 2005. PD-1 blockade inhibits hematogenous spread of poorly immunogenic tumor cells by enhanced recruitment of effector T cells. Int. Immunol. 17:133–44
    [Google Scholar]
  53. 53.
    Strome SE, Dong H, Tamura H, Voss SG, Flies DB et al. 2003. B7-H1 blockade augments adoptive T-cell immunotherapy for squamous cell carcinoma. Cancer Res 63:6501–5
    [Google Scholar]
  54. 54.
    Blank C, Brown I, Peterson AC, Spiotto M, Iwai Y et al. 2004. PD-L1/B7H-1 inhibits the effector phase of tumor rejection by T cell receptor (TCR) transgenic CD8+ T cells. Cancer Res 64:1140–45
    [Google Scholar]
  55. 55.
    Crawford A, Angelosanto JM, Kao C, Doering TA, Odorizzi PM et al. 2014. Molecular and transcriptional basis of CD4+ T cell dysfunction during chronic infection. Immunity 40:289–302
    [Google Scholar]
  56. 56.
    Moir S, Fauci AS 2014. B-cell exhaustion in HIV infection: the role of immune activation. Curr. Opin. HIV AIDS 9:472–77
    [Google Scholar]
  57. 57.
    Bi J, Tian Z 2017. NK cell exhaustion. Front. Immunol. 8:760
    [Google Scholar]
  58. 58.
    Catakovic K, Klieser E, Neureiter D, Geisberger R 2017. T cell exhaustion: from pathophysiological basics to tumor immunotherapy. Cell Commun. Signal. 15:1
    [Google Scholar]
  59. 59.
    Blackburn SD, Shin H, Freeman GJ, Wherry EJ 2008. Selective expansion of a subset of exhausted CD8 T cells by αPD-L1 blockade. PNAS 105:15016–21
    [Google Scholar]
  60. 60.
    Shin H, Blackburn SD, Blattman JN, Wherry EJ 2007. Viral antigen and extensive division maintain virus-specific CD8 T cells during chronic infection. J. Exp. Med. 204:941–49
    [Google Scholar]
  61. 61.
    Paley MA, Kroy DC, Odorizzi PM, Johnnidis JB, Dolfi DV et al. 2012. Progenitor and terminal subsets of CD8+ T cells cooperate to contain chronic viral infection. Science 338:1220–25
    [Google Scholar]
  62. 62.
    Im SJ, Hashimoto M, Gerner MY, Lee J, Kissick HT et al. 2016. Defining CD8+ T cells that provide the proliferative burst after PD-1 therapy. Nature 537:417–21
    [Google Scholar]
  63. 63.
    Fuller MJ, Zajac AJ 2003. Ablation of CD8 and CD4 T cell responses by high viral loads. J. Immunol. 170:477–86
    [Google Scholar]
  64. 64.
    Wherry EJ, Blattman JN, Murali-Krishna K, van der Most R, Ahmed R 2003. Viral persistence alters CD8 T-cell immunodominance and tissue distribution and results in distinct stages of functional impairment. J. Virol. 77:4911–27
    [Google Scholar]
  65. 65.
    Agnellini P, Wolint P, Rehr M, Cahenzli J, Karrer U, Oxenius A 2007. Impaired NFAT nuclear translocation results in split exhaustion of virus-specific CD8+ T cell functions during chronic viral infection. PNAS 104:4565–70
    [Google Scholar]
  66. 66.
    Shin H, Blackburn SD, Intlekofer AM, Kao C, Angelosanto JM et al. 2009. A role for the transcriptional repressor Blimp-1 in CD8+ T cell exhaustion during chronic viral infection. Immunity 31:309–20
    [Google Scholar]
  67. 67.
    Mackerness KJ, Cox MA, Lilly LM, Weaver CT, Harrington LE, Zajac AJ 2010. Pronounced virus-dependent activation drives exhaustion but sustains IFN-gamma transcript levels. J. Immunol. 185:3643–51
    [Google Scholar]
  68. 68.
    Fuller MJ, Khanolkar A, Tebo AE, Zajac AJ 2004. Maintenance, loss, and resurgence of T cell responses during acute, protracted, and chronic viral infections. J. Immunol. 172:4204–14
    [Google Scholar]
  69. 69.
    Wherry EJ, Ha SJ, Kaech SM, Haining WN, Sarkar S et al. 2007. Molecular signature of CD8+ T cell exhaustion during chronic viral infection. Immunity 27:670–84
    [Google Scholar]
  70. 70.
    Kao C, Oestreich KJ, Paley MA, Crawford A, Angelosanto JM et al. 2011. 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. 12:663–71
    [Google Scholar]
  71. 71.
    Tanchot C, Rocha B 1997. Peripheral selection of T cell repertoires: the role of continuous thymus output. J. Exp. Med. 186:1099–106
    [Google Scholar]
  72. 72.
    Blackburn SD, Crawford A, Shin H, Polley A, Freeman GJ, Wherry EJ 2010. Tissue-specific differences in PD-1 and PD-L1 expression during chronic viral infection: implications for CD8 T cell exhaustion. J. Virol. 84:2078–89
    [Google Scholar]
  73. 73.
    Appay V, Papagno L, Spina CA, Hansasuta P, King A et al. 2002. Dynamics of T cell responses in HIV infection. J. Immunol. 168:3660–66
    [Google Scholar]
  74. 74.
    Jameson SC, Masopust D 2009. Diversity in T cell memory: an embarrassment of riches. Immunity 31:859–71
    [Google Scholar]
  75. 75.
    Surh CD, Sprent J 2008. Homeostasis of naive and memory T cells. Immunity 29:848–62
    [Google Scholar]
  76. 76.
    Lodolce JP, Boone DL, Chai S, Swain RE, Dassopoulos T et al. 1998. IL-15 receptor maintains lymphoid homeostasis by supporting lymphocyte homing and proliferation. Immunity 9:669–76
    [Google Scholar]
  77. 77.
    Wherry EJ, Barber DL, Kaech SM, Blattman JN, Ahmed R 2004. Antigen-independent memory CD8 T cells do not develop during chronic viral infection. PNAS 101:16004–9
    [Google Scholar]
  78. 78.
    Wherry EJ, Teichgraber V, Becker TC, Masopust D, Kaech SM et al. 2003. Lineage relationship and protective immunity of memory CD8 T cell subsets. Nat. Immunol. 4:225–34
    [Google Scholar]
  79. 79.
    Radziewicz H, Ibegbu CC, Fernandez ML, Workowski KA, Obideen K et al. 2007. Liver-infiltrating lymphocytes in chronic human hepatitis C virus infection display an exhausted phenotype with high levels of PD-1 and low levels of CD127 expression. J. Virol. 81:2545–53
    [Google Scholar]
  80. 80.
    Chahroudi A, Silvestri G, Lichterfeld M 2015. T memory stem cells and HIV: a long-term relationship. Curr. HIV/AIDS Rep. 12:33–40
    [Google Scholar]
  81. 81.
    Masopust D, Vezys V, Usherwood EJ, Cauley LS, Olson S et al. 2004. Activated primary and memory CD8 T cells migrate to nonlymphoid tissues regardless of site of activation or tissue of origin. J. Immunol. 172:4875–82
    [Google Scholar]
  82. 82.
    Beltra JC, Bourbonnais S, Bedard N, Charpentier T, Boulange M et al. 2016. IL2Rβ-dependent signals drive terminal exhaustion and suppress memory development during chronic viral infection. PNAS 113:E5444–53
    [Google Scholar]
  83. 83.
    Pellegrini M, Calzascia T, Elford AR, Shahinian A, Lin AE et al. 2009. Adjuvant IL-7 antagonizes multiple cellular and molecular inhibitory networks to enhance immunotherapies. Nat. Med. 15:528–36
    [Google Scholar]
  84. 84.
    Wherry EJ, Ahmed R 2004. Memory CD8 T-cell differentiation during viral infection. J. Virol. 78:5535–45
    [Google Scholar]
  85. 85.
    Utzschneider DT, Legat A, Fuertes Marraco SA, Carrie L, Luescher I et al. 2013. T cells maintain an exhausted phenotype after antigen withdrawal and population reexpansion. Nat. Immunol. 14:603–10
    [Google Scholar]
  86. 86.
    Kasprowicz V, Kang YH, Lucas M, Schulze zur Wiesch J, Kuntzen T et al. 2010. Hepatitis C virus (HCV) sequence variation induces an HCV-specific T-cell phenotype analogous to spontaneous resolution. J. Virol. 84:1656–63
    [Google Scholar]
  87. 87.
    Jamieson BD, Yang OO, Hultin L, Hausner MA, Hultin P et al. 2003. Epitope escape mutation and decay of human immunodeficiency virus type 1-specific CTL responses. J. Immunol. 171:5372–79
    [Google Scholar]
  88. 88.
    Wieland D, Kemming J, Schuch A, Emmerich F, Knolle P et al. 2017. TCF1+ hepatitis C virus-specific CD8+ T cells are maintained after cessation of chronic antigen stimulation. Nat. Commun. 8:15050
    [Google Scholar]
  89. 89.
    Utzschneider DT, Charmoy M, Chennupati V, Pousse L, Ferreira DP 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]
  90. 90.
    Blackburn SD, Shin H, Haining WN, Zou T, Workman CJ et al. 2009. Coregulation of CD8+ T cell exhaustion by multiple inhibitory receptors during chronic viral infection. Nat. Immunol. 10:29–37
    [Google Scholar]
  91. 91.
    Kaufmann DE, Kavanagh DG, Pereyra F, Zaunders JJ, Mackey EW et al. 2007. Upregulation of CTLA-4 by HIV-specific CD4+ T cells correlates with disease progression and defines a reversible immune dysfunction. Nat. Immunol. 8:1246–54
    [Google Scholar]
  92. 92.
    Petrovas C, Casazza JP, Brenchley JM, Price DA, Gostick E et al. 2006. PD-1 is a regulator of virus-specific CD8+ T cell survival in HIV infection. J. Exp. Med. 203:2281–92
    [Google Scholar]
  93. 93.
    Trautmann L, Janbazian L, Chomont N, Said EA, Gimmig S et al. 2006. Upregulation of PD-1 expression on HIV-specific CD8+ T cells leads to reversible immune dysfunction. Nat. Med. 12:1198–202
    [Google Scholar]
  94. 94.
    Bengsch B, Seigel B, Ruhl M, Timm J, Kuntz M et al. 2010. Coexpression of PD-1, 2B4, CD160 and KLRG1 on exhausted HCV-specific CD8+ T cells is linked to antigen recognition and T cell differentiation. PLOS Pathog 6:e1000947
    [Google Scholar]
  95. 95.
    Urbani S, Amadei B, Tola D, Massari M, Schivazappa S et al. 2006. PD-1 expression in acute hepatitis C virus (HCV) infection is associated with HCV-specific CD8 exhaustion. J. Virol. 80:11398–403
    [Google Scholar]
  96. 96.
    Bengsch B, Martin B, Thimme R 2014. Restoration of HBV-specific CD8+ T cell function by PD-1 blockade in inactive carrier patients is linked to T cell differentiation. J. Hepatol. 61:1212–19
    [Google Scholar]
  97. 97.
    Velu V, Titanji K, Zhu B, Husain S, Pladevega A et al. 2009. Enhancing SIV-specific immunity in vivo by PD-1 blockade. Nature 458:206–10
    [Google Scholar]
  98. 98.
    Attanasio J, Wherry EJ 2016. Costimulatory and coinhibitory receptor pathways in infectious disease. Immunity 44:1052–68
    [Google Scholar]
  99. 99.
    MacIver NJ, Michalek RD, Rathmell JC 2013. Metabolic regulation of T lymphocytes. Annu. Rev. Immunol. 31:259–83
    [Google Scholar]
  100. 100.
    Buck MD, O'Sullivan D, Pearce EL 2015. T cell metabolism drives immunity. J. Exp. Med. 212:1345–60
    [Google Scholar]
  101. 101.
    O'Sullivan D, Pearce EL 2015. Targeting T cell metabolism for therapy. Trends Immunol 36:71–80
    [Google Scholar]
  102. 102.
    van der Windt GJ, Everts B, Chang CH, Curtis JD, Freitas TC et al. 2012. Mitochondrial respiratory capacity is a critical regulator of CD8+ T cell memory development. Immunity 36:68–78
    [Google Scholar]
  103. 103.
    Patsoukis N, Brown J, Petkova V, Liu F, Li L, Boussiotis VA 2012. Selective effects of PD-1 on Akt and Ras pathways regulate molecular components of the cell cycle and inhibit T cell proliferation. Sci. Signal. 5:ra46
    [Google Scholar]
  104. 104.
    Parry RV, Chemnitz JM, Frauwirth KA, Lanfranco AR, Braunstein I et al. 2005. CTLA-4 and PD-1 receptors inhibit T-cell activation by distinct mechanisms. Mol. Cell. Biol. 25:9543–53
    [Google Scholar]
  105. 105.
    Patsoukis N, Bardhan K, Chatterjee P, Sari D, Liu B 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]
  106. 106.
    Bengsch B, Johnson AL, Kurachi M, Odorizzi PM, Pauken KE 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]
  107. 107.
    Scharping NE, Menk AV, Moreci RS, Whetstone RD, Dadey RE et al. 2016. The tumor microenvironment represses T cell mitochondrial biogenesis to drive intratumoral T cell metabolic insufficiency and dysfunction. Immunity 45:374–88
    [Google Scholar]
  108. 108.
    Staron MM, Gray SM, Marshall HD, Parish IA, Chen JH 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]
  109. 109.
    Frauwirth KA, Thompson CB 2004. Regulation of T lymphocyte metabolism. J. Immunol. 172:4661–65
    [Google Scholar]
  110. 110.
    Hui E, Cheung J, Zhu J, Su X, Taylor MJ et al. 2017. T cell costimulatory receptor CD28 is a primary target for PD-1-mediated inhibition. Science 355:1428–33
    [Google Scholar]
  111. 111.
    Kamphorst AO, Wieland A, Nasti T, Yang S, Zhang R et al. 2017. Rescue of exhausted CD8 T cells by PD-1-targeted therapies is CD28-dependent. Science 355:1423–27
    [Google Scholar]
  112. 112.
    Schurich A, Pallett LJ, Jajbhay D, Wijngaarden J, Otano I et al. 2016. Distinct metabolic requirements of exhausted and functional virus-specific CD8 T cells in the same host. Cell Rep 16:1243–52
    [Google Scholar]
  113. 113.
    Pearce EL, Poffenberger MC, Chang CH, Jones RG 2013. Fueling immunity: insights into metabolism and lymphocyte function. Science 342:1242454
    [Google Scholar]
  114. 114.
    O'Neill LA, Pearce EJ 2016. Immunometabolism governs dendritic cell and macrophage function. J. Exp. Med. 213:15–23
    [Google Scholar]
  115. 115.
    Chang CH, Qiu J, O'Sullivan D, Buck MD, Noguchi T et al. 2015. Metabolic competition in the tumor microenvironment is a driver of cancer progression. Cell 162:1229–41
    [Google Scholar]
  116. 116.
    Kleffel S, Posch C, Barthel SR, Mueller H, Schlapbach C et al. 2015. Melanoma cell-intrinsic PD-1 receptor functions promote tumor growth. Cell 162:1242–56
    [Google Scholar]
  117. 117.
    Mineharu Y, Kamran N, Lowenstein PR, Castro MG 2014. Blockade of mTOR signaling via rapamycin combined with immunotherapy augments antiglioma cytotoxic and memory T-cell functions. Mol. Cancer Ther. 13:3024–36
    [Google Scholar]
  118. 118.
    Gammon JM, Gosselin EA, Tostanoski LH, Chiu YC, Zeng X et al. 2017. Low-dose controlled release of mTOR inhibitors maintains T cell plasticity and promotes central memory T cells. J. Control Release 263:151–61
    [Google Scholar]
  119. 119.
    Guggino G, Scotta C, Lombardi G, Dieli F, Sireci G 2017. Invariant natural killer T cells treated with rapamycin or transforming growth factor-beta acquire a regulatory function and suppress T effector lymphocytes. Cell Mol. Immunol. 14:392–94
    [Google Scholar]
  120. 120.
    Scharping NE, Menk AV, Whetstone RD, Zeng X, Delgoffe GM 2017. Efficacy of PD-1 blockade is potentiated by metformin-induced reduction of tumor hypoxia. Cancer Immunol. Res. 5:9–16
    [Google Scholar]
  121. 121.
    Alfei F, Zehn D 2017. T cell exhaustion: an epigenetically imprinted phenotypic and functional makeover. Trends Mol. Med. 23:769–71
    [Google Scholar]
  122. 122.
    Martinez GJ, Pereira RM, Aijo T, Kim EY, Marangoni F et al. 2015. The transcription factor NFAT promotes exhaustion of activated CD8+ T cells. Immunity 42:265–78
    [Google Scholar]
  123. 123.
    Scott-Browne JP, Lopez-Moyado IF, Trifari S, Wong V, Chavez L et al. 2016. Dynamic changes in chromatin accessibility occur in CD8+ T cells responding to viral infection. Immunity 45:1327–40
    [Google Scholar]
  124. 124.
    Amit I, Winter DR, Jung S 2016. The role of the local environment and epigenetics in shaping macrophage identity and their effect on tissue homeostasis. Nat. Immunol. 17:18–25
    [Google Scholar]
  125. 125.
    Monticelli S, Natoli G 2017. Transcriptional determination and functional specificity of myeloid cells: making sense of diversity. Nat. Rev. Immunol. 17:595–607
    [Google Scholar]
  126. 126.
    Mescher MF, Curtsinger JM, Agarwal P, Casey KA, Gerner M et al. 2006. Signals required for programming effector and memory development by CD8+ T cells. Immunol. Rev. 211:81–92
    [Google Scholar]
  127. 127.
    Matloubian M, Concepcion RJ, Ahmed R 1994. CD4+ T cells are required to sustain CD8+ cytotoxic T-cell responses during chronic viral infection. J. Virol. 68:8056–63
    [Google Scholar]
  128. 128.
    Mueller SN, Ahmed R 2009. High antigen levels are the cause of T cell exhaustion during chronic viral infection. PNAS 106:8623–28
    [Google Scholar]
  129. 129.
    Utzschneider DT, Alfei F, Roelli P, Barras D, Chennupati V et al. 2016. High antigen levels induce an exhausted phenotype in a chronic infection without impairing T cell expansion and survival. J. Exp. Med. 213:1819–34
    [Google Scholar]
  130. 130.
    Bucks CM, Norton JA, Boesteanu AC, Mueller YM, Katsikis PD 2009. Chronic antigen stimulation alone is sufficient to drive CD8+ T cell exhaustion. J. Immunol. 182:6697–708
    [Google Scholar]
  131. 131.
    Streeck H, Brumme ZL, Anastario M, Cohen KW, Jolin JS et al. 2008. Antigen load and viral sequence diversification determine the functional profile of HIV-1-specific CD8+ T cells. PLOS Med 5:e100
    [Google Scholar]
  132. 132.
    Reignat S, Webster GJ, Brown D, Ogg GS, King A et al. 2002. Escaping high viral load exhaustion: CD8 cells with altered tetramer binding in chronic hepatitis B virus infection. J. Exp. Med. 195:1089–101
    [Google Scholar]
  133. 133.
    El-Far M, Halwani R, Said E, Trautmann L, Doroudchi M et al. 2008. T-cell exhaustion in HIV infection. Curr. HIV/AIDS Rep. 5:13–19
    [Google Scholar]
  134. 134.
    Boni C, Fisicaro P, Valdatta C, Amadei B, Di Vincenzo P et al. 2007. Characterization of hepatitis B virus (HBV)-specific T-cell dysfunction in chronic HBV infection. J. Virol. 81:4215–25
    [Google Scholar]
  135. 135.
    Brooks DG, McGavern DB, Oldstone MB 2006. Reprogramming of antiviral T cells prevents inactivation and restores T cell activity during persistent viral infection. J. Clin. Investig. 116:1675–85
    [Google Scholar]
  136. 136.
    Angelosanto JM, Blackburn SD, Crawford A, Wherry EJ 2012. Progressive loss of memory T cell potential and commitment to exhaustion during chronic viral infection. J. Virol. 86:8161–70
    [Google Scholar]
  137. 137.
    Penaloza-MacMaster P, Provine NM, Blass E, Barouch DH 2015. CD4 T cell depletion substantially augments the rescue potential of PD-L1 blockade for deeply exhausted CD8 T cells. J. Immunol. 195:1054–63
    [Google Scholar]
  138. 138.
    Curtsinger JM, Mescher MF 2010. Inflammatory cytokines as a third signal for T cell activation. Curr. Opin. Immunol. 22:333–40
    [Google Scholar]
  139. 139.
    Joshi NS, Cui W, Chandele A, Lee HK, Urso DR et al. 2007. Inflammation directs memory precursor and short-lived effector CD8+ T cell fates via the graded expression of T-bet transcription factor. Immunity 27:281–95
    [Google Scholar]
  140. 140.
    Harty JT, Badovinac VP 2008. Shaping and reshaping CD8+ T-cell memory. Nat. Rev. Immunol. 8:107–19
    [Google Scholar]
  141. 141.
    Stelekati E, Shin H, Doering TA, Dolfi DV, Ziegler CG et al. 2014. Bystander chronic infection negatively impacts development of CD8+ T cell memory. Immunity 40:801–13
    [Google Scholar]
  142. 142.
    Wilson EB, Brooks DG 2011. The role of IL-10 in regulating immunity to persistent viral infections. Curr. Top. Microbiol. Immunol. 350:39–65
    [Google Scholar]
  143. 143.
    Brooks DG, Trifilo MJ, Edelmann KH, Teyton L, McGavern DB, Oldstone MB 2006. Interleukin-10 determines viral clearance or persistence in vivo. Nat. Med. 12:1301–9
    [Google Scholar]
  144. 144.
    Brooks DG, Ha SJ, Elsaesser H, Sharpe AH, Freeman GJ, Oldstone MB 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]
  145. 145.
    Said EA, Dupuy FP, Trautmann L, Zhang Y, Shi Y et al. 2010. Programmed death-1-induced interleukin-10 production by monocytes impairs CD4+ T cell activation during HIV infection. Nat. Med. 16:452–59
    [Google Scholar]
  146. 146.
    Couper KN, Blount DG, Riley EM 2008. IL-10: the master regulator of immunity to infection. J. Immunol. 180:5771–77
    [Google Scholar]
  147. 147.
    Yi JS, Cox MA, Zajac AJ 2010. T-cell exhaustion: characteristics, causes and conversion. Immunology 129:474–81
    [Google Scholar]
  148. 148.
    Knapp S, Hennig BJ, Frodsham AJ, Zhang L, Hellier S et al. 2003. Interleukin-10 promoter polymorphisms and the outcome of hepatitis C virus infection. Immunogenetics 55:362–69
    [Google Scholar]
  149. 149.
    Miyazoe S, Hamasaki K, Nakata K, Kajiya Y, Kitajima K et al. 2002. Influence of interleukin-10 gene promoter polymorphisms on disease progression in patients chronically infected with hepatitis B virus. Am. J. Gastroenterol. 97:2086–92
    [Google Scholar]
  150. 150.
    Shin HD, Winkler C, Stephens JC, Bream J, Young H et al. 2000. Genetic restriction of HIV-1 pathogenesis to AIDS by promoter alleles of IL10. PNAS 97:14467–72
    [Google Scholar]
  151. 151.
    Ejrnaes M, Filippi CM, Martinic MM, Ling EM, Togher LM et al. 2006. Resolution of a chronic viral infection after interleukin-10 receptor blockade. J. Exp. Med. 203:2461–72
    [Google Scholar]
  152. 152.
    Ni G, Wang T, Walton S, Zhu B, Chen S et al. 2015. Manipulating IL-10 signalling blockade for better immunotherapy. Cell Immunol 293:126–29
    [Google Scholar]
  153. 153.
    Derynck R, Zhang YE 2003. Smad-dependent and Smad-independent pathways in TGF-beta family signalling. Nature 425:577–84
    [Google Scholar]
  154. 154.
    Li MO, Wan YY, Sanjabi S, Robertson AK, Flavell RA 2006. Transforming growth factor-beta regulation of immune responses. Annu. Rev. Immunol. 24:99–146
    [Google Scholar]
  155. 155.
    Gorelik L, Constant S, Flavell RA 2002. Mechanism of transforming growth factor beta-induced inhibition of T helper type 1 differentiation. J. Exp. Med. 195:1499–505
    [Google Scholar]
  156. 156.
    Tinoco R, Alcalde V, Yang Y, Sauer K, Zuniga EI 2009. Cell-intrinsic transforming growth factor-beta signaling mediates virus-specific CD8+ T cell deletion and viral persistence in vivo. Immunity 31:145–57
    [Google Scholar]
  157. 157.
    Kekow J, Wachsman W, McCutchan JA, Gross WL, Zachariah M et al. 1991. Transforming growth factor-beta and suppression of humoral immune responses in HIV infection. J. Clin. Investig. 87:1010–6
    [Google Scholar]
  158. 158.
    Nelson DR, Gonzalez-Peralta RP, Qian K, Xu Y, Marousis CG et al. 1997. Transforming growth factor-beta 1 in chronic hepatitis C. J. Viral Hepat. 4:29–35
    [Google Scholar]
  159. 159.
    Bachmann MF, Wolint P, Walton S, Schwarz K, Oxenius A 2007. Differential role of IL-2R signaling for CD8+ T cell responses in acute and chronic viral infections. Eur. J. Immunol. 37:1502–12
    [Google Scholar]
  160. 160.
    Blattman JN, Grayson JM, Wherry EJ, Kaech SM, Smith KA, Ahmed R 2003. Therapeutic use of IL-2 to enhance antiviral T-cell responses in vivo. Nat. Med. 9:540–47
    [Google Scholar]
  161. 161.
    West EE, Jin HT, Rasheed AU, Penaloza-Macmaster P, Ha SJ et al. 2013. PD-L1 blockade synergizes with IL-2 therapy in reinvigorating exhausted T cells. J. Clin. Investig. 123:2604–15
    [Google Scholar]
  162. 162.
    Boyman O, Surh CD, Sprent J 2006. Potential use of IL-2/anti-IL-2 antibody immune complexes for the treatment of cancer and autoimmune disease. Expert Opin. Biol. Ther. 6:1323–31
    [Google Scholar]
  163. 163.
    INSIGHT-ESPRIT Study Group, SILCAAT Sci. Committee Abrams D, Levy Y, Losso MH et al. 2009. Interleukin-2 therapy in patients with HIV infection. N. Engl. J. Med. 361:1548–59
    [Google Scholar]
  164. 164.
    Caggiari L, Zanussi S, Crepaldi C, Bortolin MT, Caffau C et al. 2001. Different rates of CD4+ and CD8+ T-cell proliferation in interleukin-2-treated human immunodeficiency virus-positive subjects. Cytometry 46:233–37
    [Google Scholar]
  165. 165.
    Marchetti G, Meroni L, Molteni C, Bandera A, Franzetti F et al. 2004. Interleukin-2 immunotherapy exerts a differential effect on CD4 and CD8 T cell dynamics. AIDS 18:211–16
    [Google Scholar]
  166. 166.
    Elsaesser H, Sauer K, Brooks DG 2009. IL-21 is required to control chronic viral infection. Science 324:1569–72
    [Google Scholar]
  167. 167.
    Frohlich A, Kisielow J, Schmitz I, Freigang S, Shamshiev AT 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]
  168. 168.
    Yi JS, Du M, Zajac AJ 2009. A vital role for interleukin-21 in the control of a chronic viral infection. Science 324:1572–76
    [Google Scholar]
  169. 169.
    Micci L, Ryan ES, Fromentin R, Bosinger SE, Harper JL et al. 2015. Interleukin-21 combined with ART reduces inflammation and viral reservoir in SIV-infected macaques. J. Clin. Investig. 125:4497–513
    [Google Scholar]
  170. 170.
    Spolski R, Leonard WJ 2008. Interleukin-21: basic biology and implications for cancer and autoimmunity. Annu. Rev. Immunol. 26:57–79
    [Google Scholar]
  171. 171.
    Fahey LM, Wilson EB, Elsaesser H, Fistonich CD, McGavern DB, Brooks DG 2011. Viral persistence redirects CD4 T cell differentiation toward T follicular helper cells. J. Exp. Med. 208:987–99
    [Google Scholar]
  172. 172.
    Gu-Trantien C, Migliori E, Buisseret L, de Wind A, Brohee S et al. 2017. CXCL13-producing TFH cells link immune suppression and adaptive memory in human breast cancer. JCI Insight 2:91487
    [Google Scholar]
  173. 173.
    Gu-Trantien C, Willard-Gallo K 2017. PD-1hiCXCR5CD4+ TFH cells play defense in cancer and offense in arthritis. Trends Immunol 38:875–78
    [Google Scholar]
  174. 174.
    Xin G, Schauder DM, Lainez B, Weinstein JS, Dai Z et al. 2015. A critical role of IL-21-induced BATF in sustaining CD8-T-cell-mediated chronic viral control. Cell Rep 13:1118–24
    [Google Scholar]
  175. 175.
    Kurachi M, Barnitz RA, Yosef N, Odorizzi PM, Diiorio MA et al. 2014. The transcription factor BATF operates as an essential differentiation checkpoint in early effector CD8+ T cells. Nat. Immunol. 15:373–83
    [Google Scholar]
  176. 176.
    Quigley M, Pereyra F, Nilsson B, Porichis F, Fonseca C et al. 2010. Transcriptional analysis of HIV-specific CD8+ T cells shows that PD-1 inhibits T cell function by upregulating BATF. Nat. Med. 16:1147–51
    [Google Scholar]
  177. 177.
    McNab F, Mayer-Barber K, Sher A, Wack A, O'Garra A 2015. Type I interferons in infectious disease. Nat. Rev. Immunol. 15:87–103
    [Google Scholar]
  178. 178.
    Montoya M, Schiavoni G, Mattei F, Gresser I, Belardelli F et al. 2002. Type I interferons produced by dendritic cells promote their phenotypic and functional activation. Blood 99:3263–71
    [Google Scholar]
  179. 179.
    Papatriantafyllou M 2013. Regulatory T cells: distilling regulatory T cell inducers. Nat. Rev. Immunol. 13:546
    [Google Scholar]
  180. 180.
    Marshall HD, Urban SL, Welsh RM 2011. Virus-induced transient immune suppression and the inhibition of T cell proliferation by type I interferon. J. Virol. 85:5929–39
    [Google Scholar]
  181. 181.
    Kaser A, Nagata S, Tilg H 1999. Interferon alpha augments activation-induced T cell death by upregulation of Fas (CD95/APO-1) and Fas ligand expression. Cytokine 11:736–43
    [Google Scholar]
  182. 182.
    Wu T, Ji Y, Moseman EA, Xu HC, Manglani M 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]
  183. 183.
    Teijaro JR, Ng C, Lee AM, Sullivan BM, Sheehan KC et al. 2013. Persistent LCMV infection is controlled by blockade of type I interferon signaling. Science 340:207–11
    [Google Scholar]
  184. 184.
    Wilson EB, Yamada DH, Elsaesser H, Herskovitz J, Deng J et al. 2013. Blockade of chronic type I interferon signaling to control persistent LCMV infection. Science 340:202–7
    [Google Scholar]
  185. 185.
    Sandler NG, Bosinger SE, Estes JD, Zhu RT, Tharp GK et al. 2014. Type I interferon responses in rhesus macaques prevent SIV infection and slow disease progression. Nature 511:601–5
    [Google Scholar]
  186. 186.
    Cheng L, Ma J, Li J, Li D, Li G et al. 2017. Blocking type I interferon signaling enhances T cell recovery and reduces HIV-1 reservoirs. J. Clin. Investig. 127:269–79
    [Google Scholar]
  187. 187.
    Zhen A, Rezek V, Youn C, Lam B, Chang N et al. 2017. Targeting type I interferon-mediated activation restores immune function in chronic HIV infection. J. Clin. Investig. 127:260–68
    [Google Scholar]
  188. 188.
    Kalinski P 2012. Regulation of immune responses by prostaglandin E2. J. Immunol. 188:21–28
    [Google Scholar]
  189. 189.
    Harris SG, Padilla J, Koumas L, Ray D, Phipps RP 2002. Prostaglandins as modulators of immunity. Trends Immunol 23:144–50
    [Google Scholar]
  190. 190.
    Linnemeyer PA, Pollack SB 1993. Prostaglandin E2-induced changes in the phenotype, morphology, and lytic activity of IL-2-activated natural killer cells. J. Immunol. 150:3747–54
    [Google Scholar]
  191. 191.
    Chen JH, Perry CJ, Tsui YC, Staron MM, Parish IA et al. 2015. Prostaglandin E2 and programmed cell death 1 signaling coordinately impair CTL function and survival during chronic viral infection. Nat. Med. 21:327–34
    [Google Scholar]
  192. 192.
    Borsellino G, Kleinewietfeld M, Di Mitri D, Sternjak A, Diamantini A et al. 2007. Expression of ectonucleotidase CD39 by Foxp3+ Treg cells: hydrolysis of extracellular ATP and immune suppression. Blood 110:1225–32
    [Google Scholar]
  193. 193.
    Kobie JJ, Shah PR, Yang L, Rebhahn JA, Fowell DJ, Mosmann TR 2006. T regulatory and primed uncommitted CD4 T cells express CD73, which suppresses effector CD4 T cells by converting 5′-adenosine monophosphate to adenosine. J. Immunol. 177:6780–86
    [Google Scholar]
  194. 194.
    Horenstein AL, Chillemi A, Zaccarello G, Bruzzone S, Quarona V et al. 2013. A CD38/CD203a/CD73 ectoenzymatic pathway independent of CD39 drives a novel adenosinergic loop in human T lymphocytes. Oncoimmunology 2:e26246
    [Google Scholar]
  195. 195.
    Gupta PK, Godec J, Wolski D, Adland E, Yates K et al. 2015. CD39 expression identifies terminally exhausted CD8+ T cells. PLOS Pathog 11:e1005177
    [Google Scholar]
  196. 196.
    Simoni Y, Becht E, Fehlings M, Loh CY, Koo SL et al. 2018. Bystander CD8+ T cells are abundant and phenotypically distinct in human tumour infiltrates. Nature 557:575–79
    [Google Scholar]
  197. 197.
    Saucillo DC, Gerriets VA, Sheng J, Rathmell JC, MacIver NJ 2014. Leptin metabolically licenses T cells for activation to link nutrition and immunity. J. Immunol. 192:136–44
    [Google Scholar]
  198. 198.
    Michalek RD, Rathmell JC 2010. The metabolic life and times of a T-cell. Immunol. Rev. 236:190–202
    [Google Scholar]
  199. 199.
    Molon B, Ugel S, Del Pozzo F, Soldani C, Zilio S et al. 2011. Chemokine nitration prevents intratumoral infiltration of antigen-specific T cells. J. Exp. Med. 208:1949–62
    [Google Scholar]
  200. 200.
    Frey AB 2015. Suppression of T cell responses in the tumor microenvironment. Vaccine 33:7393–400
    [Google Scholar]
  201. 201.
    Teague TK, Marrack P, Kappler JW, Vella AT 1997. IL-6 rescues resting mouse T cells from apoptosis. J. Immunol. 158:5791–96
    [Google Scholar]
  202. 202.
    Gagnon J, Ramanathan S, Leblanc C, Cloutier A, McDonald PP, Ilangumaran S 2008. IL-6, in synergy with IL-7 or IL-15, stimulates TCR-independent proliferation and functional differentiation of CD8+ T lymphocytes. J. Immunol. 180:7958–68
    [Google Scholar]
  203. 203.
    Baxter AE, Kaufmann DE 2016. Tumor-necrosis factor is a master of T cell exhaustion. Nat. Immunol. 17:476–78
    [Google Scholar]
  204. 204.
    Woo SR, Turnis ME, Goldberg MV, Bankoti J, Selby M et al. 2012. Immune inhibitory molecules LAG-3 and PD-1 synergistically regulate T-cell function to promote tumoral immune escape. Cancer Res 72:917–27
    [Google Scholar]
  205. 205.
    Turnis ME, Sawant DV, Szymczak-Workman AL, Andrews LP, Delgoffe GM et al. 2016. Interleukin-35 limits anti-tumor immunity. Immunity 44:316–29
    [Google Scholar]
  206. 206.
    Zhang S, Zhang H, Zhao J 2009. The role of CD4 T cell help for CD8 CTL activation. Biochem. Biophys. Res. Commun. 384:405–8
    [Google Scholar]
  207. 207.
    Veiga-Parga T, Sehrawat S, Rouse BT 2013. Role of regulatory T cells during virus infection. Immunol. Rev. 255:182–96
    [Google Scholar]
  208. 208.
    Ng CT, Snell LM, Brooks DG, Oldstone MB 2013. Networking at the level of host immunity: immune cell interactions during persistent viral infections. Cell Host Microbe 13:652–64
    [Google Scholar]
  209. 209.
    Goh C, Narayanan S, Hahn YS 2013. Myeloid-derived suppressor cells: the dark knight or the joker in viral infections?. Immunol. Rev. 255:210–21
    [Google Scholar]
  210. 210.
    Waggoner SN, Cornberg M, Selin LK, Welsh RM 2011. Natural killer cells act as rheostats modulating antiviral T cells. Nature 481:394–98
    [Google Scholar]
  211. 211.
    Holderried TA, Lang PA, Kim HJ, Cantor H 2013. Genetic disruption of CD8+ Treg activity enhances the immune response to viral infection. PNAS 110:21089–94
    [Google Scholar]
  212. 212.
    Joosten SA, van Meijgaarden KE, Savage ND, de Boer T, Triebel F et al. 2007. Identification of a human CD8+ regulatory T cell subset that mediates suppression through the chemokine CC chemokine ligand 4. PNAS 104:8029–34
    [Google Scholar]
  213. 213.
    Virgin HW, Wherry EJ, Ahmed R 2009. Redefining chronic viral infection. Cell 138:30–50
    [Google Scholar]
  214. 214.
    Odorizzi PM, Wherry EJ 2012. Inhibitory receptors on lymphocytes: insights from infections. J. Immunol. 188:2957–65
    [Google Scholar]
  215. 215.
    Iwai Y, Ishida M, Tanaka Y, Okazaki T, Honjo T, Minato N 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]
  216. 216.
    Liang SC, Latchman YE, Buhlmann JE, Tomczak MF, Horwitz BH et al. 2003. Regulation of PD-1, PD-L1, and PD-L2 expression during normal and autoimmune responses. Eur. J. Immunol. 33:2706–16
    [Google Scholar]
  217. 217.
    Chemnitz JM, Parry RV, Nichols KE, June CH, Riley JL 2004. SHP-1 and SHP-2 associate with immunoreceptor tyrosine-based switch motif of programmed death 1 upon primary human T cell stimulation, but only receptor ligation prevents T cell activation. J. Immunol. 173:945–54
    [Google Scholar]
  218. 218.
    Sheppard KA, Fitz LJ, Lee JM, Benander C, George JA et al. 2004. PD-1 inhibits T-cell receptor induced phosphorylation of the ZAP70/CD3ζ signalosome and downstream signaling to PKCθ. FEBS Lett 574:37–41
    [Google Scholar]
  219. 219.
    Yokosuka T, Takamatsu M, Kobayashi-Imanishi W, Hashimoto-Tane A, Azuma M, Saito T 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]
  220. 220.
    Rota G, Niogret C, Dang AT, Barros CR, Fonta NP et al. 2018. Shp-2 is dispensable for establishing T cell exhaustion and for PD-1 signaling in vivo. Cell Rep 23:39–49
    [Google Scholar]
  221. 221.
    Odorizzi PM, Pauken KE, Paley MA, Sharpe A, Wherry EJ 2015. Genetic absence of PD-1 promotes accumulation of terminally differentiated exhausted CD8+ T cells. J. Exp. Med. 212:1125–37
    [Google Scholar]
  222. 222.
    Frebel H, Nindl V, Schuepbach RA, Braunschweiler T, Richter K et al. 2012. Programmed death 1 protects from fatal circulatory failure during systemic virus infection of mice. J. Exp. Med. 209:2485–99
    [Google Scholar]
  223. 223.
    Topalian SL, Drake CG, Pardoll DM 2015. Immune checkpoint blockade: a common denominator approach to cancer therapy. Cancer Cell 27:450–61
    [Google Scholar]
  224. 224.
    Kazandjian D, Khozin S, Blumenthal G, Zhang L, Tang S et al. 2016. Benefit-risk summary of nivolumab for patients with metastatic squamous cell lung cancer after platinum-based chemotherapy: a report from the US Food and Drug Administration. JAMA Oncol 2:118–22
    [Google Scholar]
  225. 225.
    Curran MA, Montalvo W, Yagita H, Allison JP 2010. PD-1 and CTLA-4 combination blockade expands infiltrating T cells and reduces regulatory T and myeloid cells within B16 melanoma tumors. PNAS 107:4275–80
    [Google Scholar]
  226. 226.
    Le DT, Durham JN, Smith KN, Wang H, Bartlett BR et al. 2017. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science 357:409–13
    [Google Scholar]
  227. 227.
    Lee CH, Yelensky R, Jooss K, Chan TA 2018. Update on tumor neoantigens and their utility: why it is good to be different. Trends Immunol 39:536–48
    [Google Scholar]
  228. 228.
    Turnis ME, Andrews LP, Vignali DA 2015. Inhibitory receptors as targets for cancer immunotherapy. Eur. J. Immunol. 45:1892–905
    [Google Scholar]
  229. 229.
    Johnston RJ, Comps-Agrar L, Hackney J, Yu X, Huseni M et al. 2014. The immunoreceptor TIGIT regulates antitumor and antiviral CD8+ T cell effector function. Cancer Cell 26:923–37
    [Google Scholar]
  230. 230.
    Yu X, Harden K, Gonzalez LC, Francesco M, Chiang E et al. 2009. The surface protein TIGIT suppresses T cell activation by promoting the generation of mature immunoregulatory dendritic cells. Nat. Immunol. 10:48–57
    [Google Scholar]
  231. 231.
    Chauvin JM, Pagliano O, Fourcade J, Sun Z, Wang H et al. 2015. TIGIT and PD-1 impair tumor antigen-specific CD8+ T cells in melanoma patients. J. Clin. Investig. 125:2046–58
    [Google Scholar]
  232. 232.
    Workman CJ, Dugger KJ, Vignali DA 2002. Cutting edge: molecular analysis of the negative regulatory function of lymphocyte activation gene-3. J. Immunol. 169:5392–95
    [Google Scholar]
  233. 233.
    Richter K, Agnellini P, Oxenius A 2010. On the role of the inhibitory receptor LAG-3 in acute and chronic LCMV infection. Int. Immunol. 22:13–23
    [Google Scholar]
  234. 234.
    Kuchroo VK, Dardalhon V, Xiao S, Anderson AC 2008. New roles for TIM family members in immune regulation. Nat. Rev. Immunol. 8:577–80
    [Google Scholar]
  235. 235.
    Jin HT, Anderson AC, Tan WG, West EE, Ha SJ 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]
  236. 236.
    Im SJ, Hashimoto M, Gerner MY, Lee J, Kissick HT et al. 2016. Defining CD8+ T cells that provide the proliferative burst after PD-1 therapy. Nature 537:417–20
    [Google Scholar]
  237. 237.
    Vali B, Yue FY, Jones RB, Sheth PM, Kaul R et al. 2008. HIV-specific T-cells accumulate in the liver in HCV/HIV co-infection. PLOS ONE 3:e3454
    [Google Scholar]
  238. 238.
    Golden-Mason L, Palmer BE, Kassam N, Townshend-Bulson L, Livingston S et al. 2009. Negative immune regulator Tim-3 is overexpressed on T cells in hepatitis C virus infection and its blockade rescues dysfunctional CD4+ and CD8+ T cells. J. Virol. 83:9122–30
    [Google Scholar]
  239. 239.
    Jones RB, Ndhlovu LC, Barbour JD, Sheth PM, Jha AR et al. 2008. Tim-3 expression defines a novel population of dysfunctional T cells with highly elevated frequencies in progressive HIV-1 infection. J. Exp. Med. 205:2763–79
    [Google Scholar]
  240. 240.
    McMahan RH, Golden-Mason L, Nishimura MI, McMahon BJ, Kemper M et al. 2010. Tim-3 expression on PD-1+ HCV-specific human CTLs is associated with viral persistence, and its blockade restores hepatocyte-directed in vitro cytotoxicity. J. Clin. Investig. 120:4546–57
    [Google Scholar]
  241. 241.
    Nebbia G, Peppa D, Schurich A, Khanna P, Singh HD et al. 2012. Upregulation of the Tim-3/galectin-9 pathway of T cell exhaustion in chronic hepatitis B virus infection. PLOS ONE 7:e47648
    [Google Scholar]
  242. 242.
    Wu W, Shi Y, Li S, Zhang Y, Liu Y et al. 2012. Blockade of Tim-3 signaling restores the virus-specific CD8+ T-cell response in patients with chronic hepatitis B. Eur. J. Immunol. 42:1180–91
    [Google Scholar]
  243. 243.
    Esensten JH, Helou YA, Chopra G, Weiss A, Bluestone JA 2016. CD28 costimulation: from mechanism to therapy. Immunity 44:973–88
    [Google Scholar]
  244. 244.
    Croft M 2009. The role of TNF superfamily members in T-cell function and diseases. Nat. Rev. Immunol. 9:271–85
    [Google Scholar]
  245. 245.
    Boettler T, Moeckel F, Cheng Y, Heeg M, Salek-Ardakani S et al. 2012. OX40 facilitates control of a persistent virus infection. PLOS Pathog 8:e1002913
    [Google Scholar]
  246. 246.
    Penaloza-MacMaster P, Ur Rasheed A, Iyer SS, Yagita H, Blazar BR, Ahmed R 2011. Opposing effects of CD70 costimulation during acute and chronic lymphocytic choriomeningitis virus infection of mice. J. Virol. 85:6168–74
    [Google Scholar]
  247. 247.
    Vezys V, Penaloza-MacMaster P, Barber DL, Ha SJ, Konieczny B et al. 2011. 4–1BB signaling synergizes with programmed death ligand 1 blockade to augment CD8 T cell responses during chronic viral infection. J. Immunol. 187:1634–42
    [Google Scholar]
  248. 248.
    Guedan S, Posey AD Jr, Shaw C, Wing A, Da T et al. 2018. Enhancing CAR T cell persistence through ICOS and 4–1BB costimulation. JCI Insight 3:96976
    [Google Scholar]
  249. 249.
    Dolfi DV, Mansfield KD, Polley AM, Doyle SA, Freeman GJ et al. 2013. Increased T-bet is associated with senescence of influenza virus-specific CD8 T cells in aged humans. J. Leukoc. Biol. 93:825–36
    [Google Scholar]
  250. 250.
    Xu W, Larbi A 2017. Markers of T cell senescence in humans. Int. J. Mol. Sci. 18:E1742
    [Google Scholar]
  251. 251.
    Xu L, Cao Y, Xie Z, Huang Q, Bai Q et al. 2015. The transcription factor TCF-1 initiates the differentiation of TFH cells during acute viral infection. Nat. Immunol. 16:991–99
    [Google Scholar]
  252. 252.
    Intlekofer AM, Takemoto N, Wherry EJ, Longworth SA, Northrup JT et al. 2005. Effector and memory CD8+ T cell fate coupled by T-bet and eomesodermin. Nat. Immunol. 6:1236–44
    [Google Scholar]
  253. 253.
    Pearce EL, Mullen AC, Martins GA, Krawczyk CM, Hutchins AS et al. 2003. Control of effector CD8+ T cell function by the transcription factor Eomesodermin. Science 302:1041–43
    [Google Scholar]
  254. 254.
    Sullivan BM, Juedes A, Szabo SJ, von Herrath M, Glimcher LH 2003. Antigen-driven effector CD8 T cell function regulated by T-bet. PNAS 100:15818–23
    [Google Scholar]
  255. 255.
    Banerjee A, Gordon SM, Intlekofer AM, Paley MA, Mooney EC et al. 2010. Cutting edge: The transcription factor eomesodermin enables CD8+ T cells to compete for the memory cell niche. J. Immunol. 185:4988–92
    [Google Scholar]
  256. 256.
    Intlekofer AM, Takemoto N, Kao C, Banerjee A, Schambach F et al. 2007. Requirement for T-bet in the aberrant differentiation of unhelped memory CD8+ T cells. J. Exp. Med. 204:2015–21
    [Google Scholar]
  257. 257.
    Pipkin ME, Sacks JA, Cruz-Guilloty F, Lichtenheld MG, Bevan MJ, Rao A 2010. Interleukin-2 and inflammation induce distinct transcriptional programs that promote the differentiation of effector cytolytic T cells. Immunity 32:79–90
    [Google Scholar]
  258. 258.
    Zhou X, Yu S, Zhao DM, Harty JT, Badovinac VP, Xue HH 2010. Differentiation and persistence of memory CD8+ T cells depend on T cell factor 1. Immunity 33:229–40
    [Google Scholar]
  259. 259.
    Dominguez CX, Amezquita RA, Guan T, Marshall HD, Joshi NS et al. 2015. The transcription factors ZEB2 and T-bet cooperate to program cytotoxic T cell terminal differentiation in response to LCMV viral infection. J. Exp. Med. 212:2041–56
    [Google Scholar]
  260. 260.
    Man K, Gabriel SS, Liao Y, Gloury R, Preston S et al. 2017. Transcription factor IRF4 promotes CD8+ T cell exhaustion and limits the development of memory-like T cells during chronic infection. Immunity 47:1129–41.e5
    [Google Scholar]
  261. 261.
    Crabtree GR, Olson EN 2002. NFAT signaling: choreographing the social lives of cells. Cell 109:Suppl.S67–79
    [Google Scholar]
  262. 262.
    Rao A, Luo C, Hogan PG 1997. Transcription factors of the NFAT family: regulation and function. Annu. Rev. Immunol. 15:707–47
    [Google Scholar]
  263. 263.
    Macian F, Garcia-Cozar F, Im SH, Horton HF, Byrne MC, Rao A 2002. Transcriptional mechanisms underlying lymphocyte tolerance. Cell 109:719–31
    [Google Scholar]
  264. 264.
    McHenry CR, Stenger DB, Kunze DL 1998. Inwardly rectifying K+ channels in dispersed bovine parathyroid cells. J. Surg. Res. 76:37–40
    [Google Scholar]
  265. 265.
    Macian F, Garcia-Rodriguez C, Rao A 2000. Gene expression elicited by NFAT in the presence or absence of cooperative recruitment of Fos and Jun. EMBO J 19:4783–95
    [Google Scholar]
  266. 266.
    Oestreich KJ, Yoon H, Ahmed R, Boss JM 2008. NFATc1 regulates PD-1 expression upon T cell activation. J. Immunol. 181:4832–39
    [Google Scholar]
  267. 267.
    Stelekati E, Chen A, Manne S, Kurachi M, Ali MA et al. 2018. Long-term persistence of exhausted CD8 T cells in chronic infection is regulated by microRNA-155. Cell Rep 7:2142–56
    [Google Scholar]
  268. 268.
    Hess Michelini R, Doedens AL, Goldrath AW, Hedrick SM 2013. Differentiation of CD8 memory T cells depends on Foxo1. J. Exp. Med. 210:1189–200
    [Google Scholar]
  269. 269.
    Martins GA, Hutchins AS, Reiner SL 2005. Transcriptional activators of helper T cell fate are required for establishment but not maintenance of signature cytokine expression. J. Immunol. 175:5981–85
    [Google Scholar]
  270. 270.
    Murphy TL, Tussiwand R, Murphy KM 2013. Specificity through cooperation: BATF-IRF interactions control immune-regulatory networks. Nat. Rev. Immunol. 13:499–509
    [Google Scholar]
  271. 271.
    Shi W, Man K, Smyth GK, Nutt SL, Kallies A 2014. Whole transcriptome analysis for T cell receptor-affinity and IRF4-regulated clonal expansion of T cells. Genom. Data 2:396–98
    [Google Scholar]
  272. 272.
    Man K, Miasari M, Shi W, Xin A, Henstridge DC et al. 2013. The transcription factor IRF4 is essential for TCR affinity-mediated metabolic programming and clonal expansion of T cells. Nat. Immunol. 14:1155–65
    [Google Scholar]
  273. 273.
    Yao S, Buzo BF, Pham D, Jiang L, Taparowsky EJ et al. 2013. Interferon regulatory factor 4 sustains CD8+ T cell expansion and effector differentiation. Immunity 39:833–45
    [Google Scholar]
  274. 274.
    Grusdat M, McIlwain DR, Xu HC, Pozdeev VI, Knievel J et al. 2014. IRF4 and BATF are critical for CD8+ T-cell function following infection with LCMV. Cell Death Differ 21:1050–60
    [Google Scholar]
  275. 275.
    Delpoux A, Lai CY, Hedrick SM, Doedens AL 2017. FOXO1 opposition of CD8+ T cell effector programming confers early memory properties and phenotypic diversity. PNAS 114:E8865–74
    [Google Scholar]
  276. 276.
    Haase VH 2006. The VHL/HIF oxygen-sensing pathway and its relevance to kidney disease. Kidney Int 69:1302–7
    [Google Scholar]
  277. 277.
    Menner AJ, Rauch KS, Aichele P, Pircher H, Schachtrup C, Schachtrup K 2015. Id3 controls cell death of 2B4+ virus-specific CD8+ T cells in chronic viral infection. J. Immunol. 195:2103–14
    [Google Scholar]
  278. 278.
    Buenrostro JD, Wu B, Chang HY, Greenleaf WJ 2015. ATAC-seq: a method for assaying chromatin accessibility genome-wide. Curr. Protoc. Mol. Biol. 109:21.29.1–9
    [Google Scholar]
  279. 279.
    Mognol GP, Spreafico R, Wong V, Scott-Browne JP, Togher S et al. 2017. Exhaustion-associated regulatory regions in CD8+ tumor-infiltrating T cells. PNAS 114:E2776–85
    [Google Scholar]
  280. 280.
    Lu P, Youngblood BA, Austin JW, Mohammed AU, Butler R et al. 2014. Blimp-1 represses CD8 T cell expression of PD-1 using a feed-forward transcriptional circuit during acute viral infection. J. Exp. Med. 211:515–27
    [Google Scholar]
  281. 281.
    Ghoneim HE, Fan Y, Moustaki A, Abdelsamed HA, Dash P et al. 2017. De novo epigenetic programs inhibit PD-1 blockade-mediated T cell rejuvenation. Cell 170:142–57.e19
    [Google Scholar]
  282. 282.
    Austin JW, Lu P, Majumder P, Ahmed R, Boss JM 2014. STAT3, STAT4, NFATc1, and CTCF regulate PD-1 through multiple novel regulatory regions in murine T cells. J. Immunol. 192:4876–86
    [Google Scholar]
  283. 283.
    McPherson RC, Konkel JE, Prendergast CT, Thomson JP, Ottaviano R et al. 2014. Epigenetic modification of the PD-1 (Pdcd1) promoter in effector CD4+ T cells tolerized by peptide immunotherapy. eLife 3:e03416
    [Google Scholar]
  284. 284.
    Youngblood B, Oestreich KJ, Ha SJ, Duraiswamy J, Akondy RS 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]
  285. 285.
    Zhang F, Zhou X, DiSpirito JR, Wang C, Wang Y, Shen H 2014. Epigenetic manipulation restores functions of defective CD8+ T cells from chronic viral infection. Mol. Ther. 22:1698–706
    [Google Scholar]
  286. 286.
    Leach DR, Krummel MF, Allison JP 1996. Enhancement of antitumor immunity by CTLA-4 blockade. Science 271:1734–36
    [Google Scholar]
  287. 287.
    Lonberg N, Korman AJ 2017. Masterful antibodies: checkpoint blockade. Cancer Immunol. Res. 5:275–81
    [Google Scholar]
  288. 288.
    Palmer BE, Neff CP, Lecureux J, Ehler A, Dsouza M et al. 2013. In vivo blockade of the PD-1 receptor suppresses HIV-1 viral loads and improves CD4+ T cell levels in humanized mice. J. Immunol. 190:211–19
    [Google Scholar]
  289. 289.
    Seung E, Dudek TE, Allen TM, Freeman GJ, Luster AD, Tager AM 2013. PD-1 blockade in chronically HIV-1-infected humanized mice suppresses viral loads. PLOS ONE 8:e77780
    [Google Scholar]
  290. 290.
    Zippelius A, Batard P, Rubio-Godoy V, Bioley G, Lienard D et al. 2004. Effector function of human tumor-specific CD8 T cells in melanoma lesions: a state of local functional tolerance. Cancer Res 64:2865–73
    [Google Scholar]
  291. 291.
    Sznol M, Chen L 2013. Antagonist antibodies to PD-1 and B7-H1 (PD-L1) in the treatment of advanced human cancer. Clin. Cancer Res. 19:1021–34
    [Google Scholar]
  292. 292.
    Dong H, Strome SE, Salomao DR, Tamura H, Hirano F et al. 2002. Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion. Nat. Med. 8:793–800
    [Google Scholar]
  293. 293.
    Ribas A, Wolchok JD 2018. Cancer immunotherapy using checkpoint blockade. Science 359:1350–55
    [Google Scholar]
  294. 294.
    Wolchok JD, Kluger H, Callahan MK, Postow MA, Rizvi NA et al. 2013. Nivolumab plus ipilimumab in advanced melanoma. N. Engl. J. Med. 369:122–33
    [Google Scholar]
  295. 295.
    Balachandran VP, Luksza M, Zhao JN, Makarov V, Moral JA et al. 2017. Identification of unique neoantigen qualities in long-term survivors of pancreatic cancer. Nature 551:512–16
    [Google Scholar]
  296. 296.
    Twyman-SaintVictor C, Rech AJ, Maity A, Rengan R, Pauken KE et al. 2015. Radiation and dual checkpoint blockade activate non-redundant immune mechanisms in cancer. Nature 520:373–77
    [Google Scholar]
  297. 297.
    Kamphorst AO, Pillai RN, Yang S, Nasti TH, Akondy RS et al. 2017. Proliferation of PD-1+ CD8 T cells in peripheral blood after PD-1-targeted therapy in lung cancer patients. PNAS 114:4993–98
    [Google Scholar]
  298. 298.
    Grosso JF, Goldberg MV, Getnet D, Bruno TC, Yen HR et al. 2009. Functionally distinct LAG-3 and PD-1 subsets on activated and chronically stimulated CD8 T cells. J. Immunol. 182:6659–69
    [Google Scholar]
  299. 299.
    Butler NS, Moebius J, Pewe LL, Traore B, Doumbo OK et al. 2011. Therapeutic blockade of PD-L1 and LAG-3 rapidly clears established blood-stage Plasmodium infection. Nat. Immunol. 13:188–95
    [Google Scholar]
  300. 300.
    Turnis ME, Korman AJ, Drake CG, Vignali DA 2012. Combinatorial Immunotherapy: PD-1 may not be LAG-ing behind any more. Oncoimmunology 1:1172–74
    [Google Scholar]
  301. 301.
    Chong EA, Melenhorst JJ, Lacey SF, Ambrose DE, Gonzalez V et al. 2017. PD-1 blockade modulates chimeric antigen receptor (CAR)-modified T cells: refueling the CAR. Blood 129:1039–41
    [Google Scholar]
  302. 302.
    Ren J, Liu X, Fang C, Jiang S, June CH, Zhao Y 2017. Multiplex genome editing to generate universal CAR T cells resistant to PD-1 inhibition. Clin. Cancer Res. 23:2255–66
    [Google Scholar]
  303. 303.
    Kurachi M, Kurachi J, Chen Z, Johnson J, Khan O et al. 2017. Optimized retroviral transduction of mouse T cells for in vivo assessment of gene function. Nat. Protoc. 12:1980–98
    [Google Scholar]
  304. 304.
    Pegram HJ, Andrews DM, Smyth MJ, Darcy PK, Kershaw MH 2011. Activating and inhibitory receptors of natural killer cells. Immunol. Cell Biol. 89:216–24
    [Google Scholar]
  305. 305.
    Sharma P, Allison JP 2015. The future of immune checkpoint therapy. Science 348:56–61
    [Google Scholar]
  306. 306.
    Guo Z, Wang X, Cheng D, Xia Z, Luan M, Zhang S 2014. PD-1 blockade and OX40 triggering synergistically protects against tumor growth in a murine model of ovarian cancer. PLOS ONE 9:e89350
    [Google Scholar]
  307. 307.
    Jure-Kunkel M, Masters G, Girit E, Dito G, Lee F et al. 2013. Synergy between chemotherapeutic agents and CTLA-4 blockade in preclinical tumor models. Cancer Immunol. Immunother. 62:1533–45
    [Google Scholar]
  308. 308.
    Budhu S, Schaer DA, Li Y, Toledo-Crow R, Panageas K et al. 2017. Blockade of surface-bound TGF-β on regulatory T cells abrogates suppression of effector T cell function in the tumor microenvironment. Sci. Signal 10:eaak9702
    [Google Scholar]
  309. 309.
    Mittal D, Young A, Stannard K, Yong M, Teng MW et al. 2014. Antimetastatic effects of blocking PD-1 and the adenosine A2A receptor. Cancer Res 74:3652–58
    [Google Scholar]
  310. 310.
    Gay F, D'Agostino M, Giaccone L, Genuardi M, Festuccia M et al. 2017. Immuno-oncologic approaches: CAR-T cells and checkpoint inhibitors. Clin. Lymphoma Myeloma Leuk. 17:471–78
    [Google Scholar]
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