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Seminars in Immunopathology

Erschienen in:

15.04.2019 | Review

CD8⁺ T cell exhaustion

verfasst von: Makoto Kurachi

Erschienen in: Seminars in Immunopathology | Ausgabe 3/2019

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Abstract

CD8⁺ T cells are important for the protective immunity against intracellular pathogens and tumor. In the case of chronic infection or cancer, CD8⁺ T cells are exposed to persistent antigen and/or inflammatory signals. This excessive amount of signals often leads CD8⁺ T cells to gradual deterioration of T cell function, a state called “exhaustion.” Exhausted T cells are characterized by progressive loss of effector functions (cytokine production and killing function), expression of multiple inhibitory receptors (such as PD-1 and LAG3), dysregulated metabolism, poor memory recall response, and homeostatic proliferation. These altered functions are closely related with altered transcriptional program and epigenetic landscape that clearly distinguish exhausted T cells from normal effector and memory T cells. T cell exhaustion is often associated with inefficient control of persisting infections and cancers, but re-invigoration of exhausted T cells with inhibitory receptor blockade can promote improved immunity and disease outcome. Accumulating evidences support the therapeutic potential of targeting exhausted T cells. However, exhausted T cells comprise heterogenous cell population with distinct responsiveness to intervention. Understanding molecular mechanism of T cell exhaustion is essential to establish rational immunotherapeutic interventions.

Kaech SM, Cui W (2012) Transcriptional control of effector and memory CD8+ T cell differentiation. Nat Rev Immunol 12(11):749–761. https://doi.org/10.1038/nri3307 CrossRefPubMedPubMedCentral

Wherry EJ, Kurachi M (2015) Molecular and cellular insights into T cell exhaustion. Nat Rev Immunol 15(8):486–499. https://doi.org/10.1038/nri3862 CrossRefPubMedPubMedCentral

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(6):1130–1144. https://doi.org/10.1016/j.immuni.2012.08.021 CrossRefPubMedPubMedCentral

Attanasio J, Wherry EJ (2016) Costimulatory and coinhibitory receptor pathways in infectious disease. Immunity 44(5):1052–1068. https://doi.org/10.1016/j.immuni.2016.04.022 CrossRefPubMedPubMedCentral

Kao C, Oestreich KJ, Paley MA, Crawford A, Angelosanto JM, Ali M-AA, Intlekofer AM, Boss JM, Reiner SL, Weinmann AS, Wherry EJ (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(7):663–671. https://doi.org/10.1038/ni.2046 CrossRefPubMedPubMedCentral

Paley MA, Kroy DC, Odorizzi PM, Johnnidis JB, Dolfi DV, Barnett BE, Bikoff EK, Robertson EJ, Lauer GM, Reiner SL, Wherry EJ (2012) Progenitor and terminal subsets of CD8+ T cells cooperate to contain chronic viral infection. Science 338(6111):1220–1225. https://doi.org/10.1126/science.1229620 CrossRefPubMedPubMedCentral

Bengsch B, Johnson AL, Kurachi M, Odorizzi PM, Pauken KE, Attanasio J, Stelekati E, McLane LM, Paley MA, Delgoffe GM, Wherry EJ (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(2):358–373. https://doi.org/10.1016/j.immuni.2016.07.008 CrossRefPubMedPubMedCentral

Sen DR, Kaminski J, Barnitz RA, Kurachi M, Gerdemann U, Yates KB, Tsao HW, Godec J, LaFleur MW, Brown FD, Tonnerre P, Chung RT, Tully DC, Allen TM, Frahm N, Lauer GM, Wherry EJ, Yosef N, Haining WN (2016) The epigenetic landscape of T cell exhaustion. Science 354(6316):1165–1169. https://doi.org/10.1126/science.aae0491 CrossRefPubMedPubMedCentral

Pauken KE, Sammons MA, Odorizzi PM, Manne S, Godec J, Khan O, Drake AM, Chen Z, Sen DR, Kurachi M, Barnitz RA, Bartman C, Bengsch B, Huang AC, Schenkel JM, Vahedi G, Haining WN, Berger SL, Wherry EJ (2016) Epigenetic stability of exhausted T cells limits durability of reinvigoration by PD-1 blockade. Science 354(6316):1160–1165. https://doi.org/10.1126/science.aaf2807 CrossRefPubMedPubMedCentral

10.

Barber DL, Wherry EJ, Masopust D, Zhu B, Allison JP, Sharpe AH, Freeman GJ, Ahmed R (2006) Restoring function in exhausted CD8 T cells during chronic viral infection. Nature 439(7077):682–687. https://doi.org/10.1038/nature04444 CrossRefPubMed

11.

Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, Powderly JD, Carvajal RD, Sosman JA, Atkins MB, Leming PD, Spigel DR, Antonia SJ, Horn L, Drake CG, Pardoll DM, Chen L, Sharfman WH, Anders RA, Taube JM, McMiller TL, Xu H, Korman AJ, Jure-Kunkel M, Agrawal S, McDonald D, Kollia GD, Gupta A, Wigginton JM, Sznol M (2012) Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med 366(26):2443–2454. https://doi.org/10.1056/NEJMoa1200690 CrossRefPubMedPubMedCentral

12.

Hamid O, Robert C, Daud A, Hodi FS, Hwu WJ, Kefford R, Wolchok JD, Hersey P, Joseph RW, Weber JS, Dronca R, Gangadhar TC, Patnaik A, Zarour H, Joshua AM, Gergich K, Elassaiss-Schaap J, Algazi A, Mateus C, Boasberg P, Tumeh PC, Chmielowski B, Ebbinghaus SW, Li XN, Kang SP, Ribas A (2013) Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma. N Engl J Med 369(2):134–144. https://doi.org/10.1056/NEJMoa1305133 CrossRefPubMedPubMedCentral

13.

Brahmer JR, Tykodi SS, Chow LQ, Hwu WJ, Topalian SL, Hwu P, Drake CG, Camacho LH, Kauh J, Odunsi K, Pitot HC, Hamid O, Bhatia S, Martins R, Eaton K, Chen S, Salay TM, Alaparthy S, Grosso JF, Korman AJ, Parker SM, Agrawal S, Goldberg SM, Pardoll DM, Gupta A, Wigginton JM (2012) Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med 366(26):2455–2465. https://doi.org/10.1056/NEJMoa1200694 CrossRefPubMedPubMedCentral

14.

Gardiner D, Lalezari J, Lawitz E, DiMicco M, Ghalib R, Reddy KR, Chang KM, Sulkowski M, Marro SO, Anderson J, He B, Kansra V, McPhee F, Wind-Rotolo M, Grasela D, Selby M, Korman AJ, Lowy I (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(5):e63818. https://doi.org/10.1371/journal.pone.0063818 CrossRefPubMedPubMedCentral

15.

Gallimore A, Glithero A, Godkin A, Tissot AC, Pluckthun A, Elliott T, Hengartner H, Zinkernagel R (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(9):1383–1393CrossRefPubMedPubMedCentral

16.

Lee PP, Yee C, Savage PA, Fong L, Brockstedt D, Weber JS, Johnson D, Swetter S, Thompson J, Greenberg PD, Roederer M, Davis MM (1999) Characterization of circulating T cells specific for tumor-associated antigens in melanoma patients. Nat Med 5(6):677–685. https://doi.org/10.1038/9525 CrossRefPubMed

17.

Wherry EJ (2011) T cell exhaustion. Nat Immunol 131(6):492–499. https://doi.org/10.1038/ni.2035 CrossRef

18.

Trautmann L, Janbazian L, Chomont N, Said EA, Gimmig S, Bessette B, Boulassel M-R, Delwart E, Sepulveda H, Balderas RS, Routy J-P, Haddad EK, Sekaly R-P (2006) Upregulation of PD-1 expression on HIV-specific CD8+ T cells leads to reversible immune dysfunction. Nat Med 12(10):1198–1202. https://doi.org/10.1038/nm1482 CrossRefPubMed

19.

Day CL, Kaufmann DE, Kiepiela P, Brown JA, Moodley ES, Reddy S, Mackey EW, Miller JD, Leslie AJ, DePierres C, Mncube Z, Duraiswamy J, Zhu B, Eichbaum Q, Altfeld M, Wherry EJ, Coovadia HM, Goulder PJ, Klenerman P, Ahmed R, Freeman GJ, Walker BD (2006) PD-1 expression on HIV-specific T cells is associated with T-cell exhaustion and disease progression. Nature 443(7109):350–354. https://doi.org/10.1038/nature05115 CrossRefPubMed

20.

Wherry EJ, Ha S-J, Kaech SM, Haining WN, Sarkar S, Kalia V, Subramaniam S, Blattman JN, Barber DL, Ahmed R (2007) Molecular signature of CD8+ T cell exhaustion during chronic viral infection. Immunity 27(4):670–684. https://doi.org/10.1016/j.immuni.2007.09.006 CrossRefPubMed

21.

Crawford A, Angelosanto JM, Kao C, Doering TA, Odorizzi PM, Barnett BE, Wherry EJ (2014) Molecular and transcriptional basis of CD4(+) T cell dysfunction during chronic infection. Immunity 40(2):289–302. https://doi.org/10.1016/j.immuni.2014.01.005 CrossRefPubMedPubMedCentral

22.

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(12):8056–8063PubMedPubMedCentral

23.

Quigley M, Pereyra F, Nilsson B, Porichis F, Fonseca C, Eichbaum Q, Julg B, Jesneck JL, Brosnahan K, Imam S, Russell K, Toth I, Piechocka-Trocha A, Dolfi D, Angelosanto J, Crawford A, Shin H, Kwon DS, Zupkosky J, Francisco L, Freeman GJ, Wherry EJ, Kaufmann DE, Walker BD, Ebert B, Haining WN (2010) Transcriptional analysis of HIV-specific CD8+ T cells shows that PD-1 inhibits T cell function by upregulating BATF. Nat Med 16(10):1147–1151. https://doi.org/10.1038/nm.2232 CrossRefPubMedPubMedCentral

24.

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(8):4911–4927CrossRefPubMedPubMedCentral

25.

Blackburn SD, Shin H, Haining WN, Zou T, Workman CJ, Polley A, Betts MR, Freeman GJ, Vignali DAA, Wherry EJ (2009) Coregulation of CD8+ T cell exhaustion by multiple inhibitory receptors during chronic viral infection. Nat Immunol 10(1):29–37. https://doi.org/10.1038/ni.1679 CrossRefPubMed

26.

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. Proc Natl Acad Sci U S A 104(11):4565–4570. https://doi.org/10.1073/pnas.0610335104 CrossRefPubMedPubMedCentral

27.

Chiu YL, Shan L, Huang H, Haupt C, Bessell C, Canaday DH, Zhang H, Ho YC, Powell JD, Oelke M, Margolick JB, Blankson JN, Griffin DE, Schneck JP (2013) Sprouty-2 regulates HIV-specific T cell polyfunctionality. J Clin Invest 124:198–208. https://doi.org/10.1172/jci70510 CrossRefPubMedCentral

28.

Oestreich KJ, Yoon H, Ahmed R, Boss JM (2008) NFATc1 regulates PD-1 expression upon T cell activation. J Immunol 181(7):4832–4839CrossRefPubMed

29.

Honda T, Egen JG, Lammermann T, Kastenmuller W, Torabi-Parizi P, Germain RN (2014) Tuning of antigen sensitivity by T cell receptor-dependent negative feedback controls T cell effector function in inflamed tissues. Immunity 40(2):235–247. https://doi.org/10.1016/j.immuni.2013.11.017 CrossRefPubMedPubMedCentral

30.

Okazaki T, Chikuma S, Iwai Y, Fagarasan S, Honjo T (2013) A rheostat for immune responses: the unique properties of PD-1 and their advantages for clinical application. Nat Immunol 14(12):1212–1218. https://doi.org/10.1038/ni.2762 CrossRefPubMed

31.

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(3):239–245. https://doi.org/10.1038/ni1443 CrossRefPubMed

32.

Odorizzi PM, Wherry EJ (2012) Inhibitory receptors on lymphocytes: insights from infections. J Immunol 188(7):2957–2965. https://doi.org/10.4049/jimmunol.1100038 CrossRefPubMed

33.

Araki K, Youngblood B, Ahmed R (2014) Programmed cell death 1-directed immunotherapy for enhancing T-cell function. Cold Spring Harb Symp Quant Biol 78:239–247. https://doi.org/10.1101/sqb.78.019869 CrossRef

34.

Petrovas C, Casazza JP, Brenchley JM, Price DA, Gostick E, Adams WC, Precopio ML, Schacker T, Roederer M, Douek DC, Koup RA (2006) PD-1 is a regulator of virus-specific CD8+ T cell survival in HIV infection. J Exp Med 203(10):2281–2292. https://doi.org/10.1084/jem.20061496 CrossRefPubMedPubMedCentral

35.

Pentcheva-Hoang T, Egen JG, Wojnoonski K, Allison JP (2004) B7-1 and B7-2 selectively recruit CTLA-4 and CD28 to the immunological synapse. Immunity 21(3):401–413. https://doi.org/10.1016/j.immuni.2004.06.017 CrossRefPubMed

36.

Parry RV, Chemnitz JM, Frauwirth KA, Lanfranco AR, Braunstein I, Kobayashi SV, Linsley PS, Thompson CB, Riley JL (2005) CTLA-4 and PD-1 receptors inhibit T-cell activation by distinct mechanisms. Mol Cell Biol 25(21):9543–9553. https://doi.org/10.1128/MCB.25.21.9543-9553.2005 CrossRefPubMedPubMedCentral

37.

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(6):1201–1217. https://doi.org/10.1084/jem.20112741 CrossRefPubMedPubMedCentral

38.

Clayton KL, Haaland MS, Douglas-Vail MB, Mujib S, Chew GM, Ndhlovu LC, Ostrowski MA (2014) T cell Ig and mucin domain-containing protein 3 is recruited to the immune synapse, disrupts stable synapse formation, and associates with receptor phosphatases. J Immunol 192(2):782–791. https://doi.org/10.4049/jimmunol.1302663 CrossRefPubMed

39.

Zinselmeyer BH, Heydari S, Sacristan C, Nayak D, Cammer M, Herz J, Cheng X, Davis SJ, Dustin ML, McGavern DB (2013) PD-1 promotes immune exhaustion by inducing antiviral T cell motility paralysis. J Exp Med 210(4):757–774. https://doi.org/10.1084/jem.20121416 CrossRefPubMedPubMedCentral

40.

Riley JL (2009) PD-1 signaling in primary T cells. Immunol Rev 229(1):114–125. https://doi.org/10.1111/j.1600-065X.2009.00767.x CrossRefPubMedPubMedCentral

41.

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(2):945–954CrossRefPubMed

42.

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(230):ra46. https://doi.org/10.1126/scisignal.2002796 CrossRefPubMedPubMedCentral

43.

Patsoukis N, Sari D, Boussiotis VA (2012) PD-1 inhibits T cell proliferation by upregulating p27 and p15 and suppressing Cdc25A. Cell Cycle (Georgetown, Tex) 11(23):4305–4309. https://doi.org/10.4161/cc.22135 CrossRef

44.

Duraiswamy J, Ibegbu CC, Masopust D, Miller JD, Araki K, Doho GH, Tata P, Gupta S, Zilliox MJ, Nakaya HI, Pulendran B, Haining WN, Freeman GJ, Ahmed R (2011) Phenotype, function, and gene expression profiles of programmed death-1(hi) CD8 T cells in healthy human adults. J Immunol 186(7):4200–4212. https://doi.org/10.4049/jimmunol.1001783 CrossRefPubMed

45.

Dolfi DV, Mansfield KD, Polley AM, Doyle SA, Freeman GJ, Pircher H, Schmader KE, Wherry EJ (2013) Increased T-bet is associated with senescence of influenza virus-specific CD8 T cells in aged humans. J Leukoc Biol 93(6):825–836. https://doi.org/10.1189/jlb.0912438 CrossRefPubMedPubMedCentral

46.

Blackburn SD, Shin H, Freeman GJ, Wherry EJ (2008) Selective expansion of a subset of exhausted CD8 T cells by anti-PD-L1 blockade. Proc Natl Acad Sci U S A 105(39):15016–15021. https://doi.org/10.1073/pnas.0801497105 CrossRefPubMedPubMedCentral

47.

Blattman JN, Wherry EJ, Ha SJ, van der Most RG, Ahmed R (2009) Impact of epitope escape on PD-1 expression and CD8 T-cell exhaustion during chronic infection. J Virol 83(9):4386–4394. https://doi.org/10.1128/JVI.02524-08 CrossRefPubMedPubMedCentral

48.

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(15):8161–8170. https://doi.org/10.1128/JVI.00889-12 CrossRefPubMedPubMedCentral

49.

Utzschneider DT, Legat A, Fuertes Marraco SA, Carrie L, Luescher I, Speiser DE, Zehn D (2013) T cells maintain an exhausted phenotype after antigen withdrawal and population reexpansion. Nat Immunol 14(6):603–610. https://doi.org/10.1038/ni.2606 CrossRefPubMed

50.

Youngblood B, Oestreich KJ, Ha SJ, Duraiswamy J, Akondy RS, West EE, Wei Z, Lu P, Austin JW, Riley JL, Boss JM, Ahmed R (2011) Chronic virus infection enforces demethylation of the locus that encodes PD-1 in antigen-specific CD8(+) T cells. Immunity 35(3):400–412. https://doi.org/10.1016/j.immuni.2011.06.015 CrossRefPubMedPubMedCentral

51.

Butler NS, Moebius J, Pewe LL, Traore B, Doumbo OK, Tygrett LT, Waldschmidt TJ, Crompton PD, Harty JT (2011) Therapeutic blockade of PD-L1 and LAG-3 rapidly clears established blood-stage Plasmodium infection. Nat Immunol 13(2):188–195. https://doi.org/10.1038/ni.2180 CrossRefPubMedPubMedCentral

52.

Grosso JF, Goldberg MV, Getnet D, Bruno TC, Yen HR, Pyle KJ, Hipkiss E, Vignali DA, Pardoll DM, Drake CG (2009) Functionally distinct LAG-3 and PD-1 subsets on activated and chronically stimulated CD8 T cells. J Immunol 182(11):6659–6669. https://doi.org/10.4049/jimmunol.0804211 CrossRefPubMed

53.

Matsuzaki J, Gnjatic S, Mhawech-Fauceglia P, Beck A, Miller A, Tsuji T, Eppolito C, Qian F, Lele S, Shrikant P, Old LJ, Odunsi K (2010) Tumor-infiltrating NY-ESO-1-specific CD8+ T cells are negatively regulated by LAG-3 and PD-1 in human ovarian cancer. Proc Natl Acad Sci U S A 107(17):7875–7880. https://doi.org/10.1073/pnas.1003345107 CrossRefPubMedPubMedCentral

54.

Kaufmann DE, Kavanagh DG, Pereyra F, Zaunders JJ, Mackey EW, Miura T, Palmer S, Brockman M, Rathod A, Piechocka-Trocha A, Baker B, Zhu B, Le Gall S, Waring MT, Ahern R, Moss K, Kelleher AD, Coffin JM, Freeman GJ, Rosenberg ES, Walker BD (2007) Upregulation of CTLA-4 by HIV-specific CD4+ T cells correlates with disease progression and defines a reversible immune dysfunction. Nat Immunol 8(11):1246–1254. https://doi.org/10.1038/ni1515 CrossRefPubMed

55.

Nakamoto N, Cho H, Shaked A, Olthoff K, Valiga ME, Kaminski M, Gostick E, Price DA, Freeman GJ, Wherry EJ, Chang KM (2009) Synergistic reversal of intrahepatic HCV-specific CD8 T cell exhaustion by combined PD-1/CTLA-4 blockade. PLoS Pathog 5(2):e1000313. https://doi.org/10.1371/journal.ppat.1000313 CrossRefPubMedPubMedCentral

56.

Jin HT, Anderson AC, Tan WG, West EE, Ha SJ, Araki K, Freeman GJ, Kuchroo VK, Ahmed R (2010) Cooperation of Tim-3 and PD-1 in CD8 T-cell exhaustion during chronic viral infection. Proc Natl Acad Sci U S A 107(33):14733–14738. https://doi.org/10.1073/pnas.1009731107 CrossRefPubMedPubMedCentral

57.

Kassu A, Marcus RA, D'Souza MB, Kelly-McKnight EA, Golden-Mason L, Akkina R, Fontenot AP, Wilson CC, Palmer BE (2010) Regulation of virus-specific CD4+ T cell function by multiple costimulatory receptors during chronic HIV infection. J Immunol 185(5):3007–3018. https://doi.org/10.4049/jimmunol.1000156 CrossRefPubMed

58.

Sakuishi K, Apetoh L, Sullivan JM, Blazar BR, Kuchroo VK, Anderson AC (2010) Targeting Tim-3 and PD-1 pathways to reverse T cell exhaustion and restore anti-tumor immunity. J Exp Med 207(10):2187–2194. https://doi.org/10.1084/jem.20100643 CrossRefPubMedPubMedCentral

59.

Fourcade J, Sun Z, Benallaoua M, Guillaume P, Luescher IF, Sander C, Kirkwood JM, Kuchroo V, Zarour HM (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(10):2175–2186. https://doi.org/10.1084/jem.20100637 CrossRefPubMedPubMedCentral

60.

Wolchok JD, Kluger H, Callahan MK, Postow MA, Rizvi NA, Lesokhin AM, Segal NH, Ariyan CE, Gordon RA, Reed K, Burke MM, Caldwell A, Kronenberg SA, Agunwamba BU, Zhang X, Lowy I, Inzunza HD, Feely W, Horak CE, Hong Q, Korman AJ, Wigginton JM, Gupta A, Sznol M (2013) Nivolumab plus ipilimumab in advanced melanoma. N Engl J Med 369(2):122–133. https://doi.org/10.1056/NEJMoa1302369 CrossRefPubMedPubMedCentral

61.

Wang C, McPherson AJ, Jones RB, Kawamura KS, Lin GH, Lang PA, Ambagala T, Pellegrini M, Calzascia T, Aidarus N, Elford AR, Yue FY, Kremmer E, Kovacs CM, Benko E, Tremblay C, Routy JP, Bernard NF, Ostrowski MA, Ohashi PS, Watts TH (2012) Loss of the signaling adaptor TRAF1 causes CD8+ T cell dysregulation during human and murine chronic infection. J Exp Med 209(1):77–91. https://doi.org/10.1084/jem.20110675 CrossRefPubMedPubMedCentral

62.

Matter M, Odermatt B, Yagita H, Nuoffer JM, Ochsenbein AF (2006) Elimination of chronic viral infection by blocking CD27 signaling. J Exp Med 203(9):2145–2155. https://doi.org/10.1084/jem.20060651 CrossRefPubMedPubMedCentral

63.

Isogawa M, Chung J, Murata Y, Kakimi K, Chisari FV (2013) CD40 activation rescues antiviral CD8+ T cells from PD-1-mediated exhaustion. PLoS Pathog 9(7):e1003490. https://doi.org/10.1371/journal.ppat.1003490 CrossRefPubMedPubMedCentral

64.

Beatty GL, Chiorean EG, Fishman MP, Saboury B, Teitelbaum UR, Sun W, Huhn RD, Song W, Li D, Sharp LL, Torigian DA, O'Dwyer PJ, Vonderheide RH (2011) CD40 agonists alter tumor stroma and show efficacy against pancreatic carcinoma in mice and humans. Science 331(6024):1612–1616. https://doi.org/10.1126/science.1198443 CrossRefPubMedPubMedCentral

65.

Vezys V, Penaloza-MacMaster P, Barber DL, Ha SJ, Konieczny B, Freeman GJ, Mittler RS, Ahmed R (2011) 4-1BB signaling synergizes with programmed death ligand 1 blockade to augment CD8 T cell responses during chronic viral infection. J Immunol 187(4):1634–1642. https://doi.org/10.4049/jimmunol.1100077 CrossRefPubMed

66.

Ha SJ, Mueller SN, Wherry EJ, Barber DL, Aubert RD, Sharpe AH, Freeman GJ, Ahmed R (2008) Enhancing therapeutic vaccination by blocking PD-1-mediated inhibitory signals during chronic infection. J Exp Med 205(3):543–555. https://doi.org/10.1084/jem.20071949 CrossRefPubMedPubMedCentral

67.

West EE, Jin HT, Rasheed AU, Penaloza-Macmaster P, Ha SJ, Tan WG, Youngblood B, Freeman GJ, Smith KA, Ahmed R (2013) PD-L1 blockade synergizes with IL-2 therapy in reinvigorating exhausted T cells. J Clin Invest 123(6):2604–2615. https://doi.org/10.1172/JCI67008 CrossRefPubMedPubMedCentral

68.

Penaloza-MacMaster P, Kamphorst AO, Wieland A, Araki K, Iyer SS, West EE, O'Mara L, Yang S, Konieczny BT, Sharpe AH, Freeman GJ, Rudensky AY, Ahmed R (2014) Interplay between regulatory T cells and PD-1 in modulating T cell exhaustion and viral control during chronic LCMV infection. J Exp Med 211(9):1905–1918. https://doi.org/10.1084/jem.20132577 CrossRefPubMedPubMedCentral

69.

Brooks DG, Trifilo MJ, Edelmann KH, Teyton L, McGavern DB, Oldstone MBA (2006) Interleukin-10 determines viral clearance or persistence in vivo. Nat Med 12(11):1301–1309. https://doi.org/10.1038/nm1492 CrossRefPubMedPubMedCentral

70.

Ejrnaes M, Filippi CM, Martinic MM, Ling EM, Togher LM, Crotty S, von Herrath MG (2006) Resolution of a chronic viral infection after interleukin-10 receptor blockade. J Exp Med 203(11):2461–2472. https://doi.org/10.1084/jem.20061462 CrossRefPubMedPubMedCentral

71.

Ng CT, Oldstone MB (2012) Infected CD8alpha-dendritic cells are the predominant source of IL-10 during establishment of persistent viral infection. Proc Natl Acad Sci U S A 109(35):14116–14121. https://doi.org/10.1073/pnas.1211910109 CrossRefPubMedPubMedCentral

72.

Said EA, Dupuy FP, Trautmann L, Zhang Y, Shi Y, El-Far M, Hill BJ, Noto A, Ancuta P, Peretz Y, Fonseca SG, Van Grevenynghe J, Boulassel MR, Bruneau J, Shoukry NH, Routy JP, Douek DC, Haddad EK, Sekaly RP (2010) Programmed death-1-induced interleukin-10 production by monocytes impairs CD4+ T cell activation during HIV infection. Nat Med 16(4):452–459. https://doi.org/10.1038/nm.2106 CrossRefPubMedPubMedCentral

73.

Richter K, Perriard G, Behrendt R, Schwendener RA, Sexl V, Dunn R, Kamanaka M, Flavell RA, Roers A, Oxenius A (2013) Macrophage and T cell produced IL-10 promotes viral chronicity. PLoS Pathog 9(11):e1003735. https://doi.org/10.1371/journal.ppat.1003735 CrossRefPubMedPubMedCentral

74.

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. Proc Natl Acad Sci U S A 105(51):20428–20433. https://doi.org/10.1073/pnas.0811139106 CrossRefPubMedPubMedCentral

75.

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(1):145–157. https://doi.org/10.1016/j.immuni.2009.06.015 CrossRefPubMedPubMedCentral

76.

Garidou L, Heydari S, Gossa S, McGavern DB (2012) Therapeutic blockade of transforming growth factor beta fails to promote clearance of a persistent viral infection. J Virol 86(13):7060–7071. https://doi.org/10.1128/JVI.00164-12 CrossRefPubMedPubMedCentral

77.

Boettler T, Cheng Y, Ehrhardt K, von Herrath M (2012) TGF-beta blockade does not improve control of an established persistent viral infection. Viral Immunol 25(3):232–238. https://doi.org/10.1089/vim.2011.0079 CrossRefPubMedPubMedCentral

78.

Curtsinger JM, Mescher MF (2010) Inflammatory cytokines as a third signal for T cell activation. Curr Opin Immunol 22(3):333–340. https://doi.org/10.1016/j.coi.2010.02.013 CrossRefPubMedPubMedCentral

79.

Teijaro JR, Ng C, Lee AM, Sullivan BM, Sheehan KC, Welch M, Schreiber RD, de la Torre JC, Oldstone MB (2013) Persistent LCMV infection is controlled by blockade of type I interferon signaling. Science 340(6129):207–211. https://doi.org/10.1126/science.1235214 CrossRefPubMedPubMedCentral

80.

Wilson EB, Yamada DH, Elsaesser H, Herskovitz J, Deng J, Cheng G, Aronow BJ, Karp CL, Brooks DG (2013) Blockade of chronic type I interferon signaling to control persistent LCMV infection. Science 340(6129):202–207. https://doi.org/10.1126/science.1235208 CrossRefPubMedPubMedCentral

81.

Gerner MY, Heltemes-Harris LM, Fife BT, Mescher MF (2013) Cutting edge: IL-12 and type I IFN differentially program CD8 T cells for programmed death 1 re-expression levels and tumor control. J Immunol 191(3):1011–1015. https://doi.org/10.4049/jimmunol.1300652 CrossRefPubMed

82.

Stelekati E, Shin H, Doering TA, Dolfi DV, Ziegler CG, Beiting DP, Dawson L, Liboon J, Wolski D, Ali MA, Katsikis PD, Shen H, Roos DS, Haining WN, Lauer GM, Wherry EJ (2014) Bystander chronic infection negatively impacts development of CD8(+) T cell memory. Immunity 40(5):801–813. https://doi.org/10.1016/j.immuni.2014.04.010 CrossRefPubMedPubMedCentral

83.

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(4):2078–2089. https://doi.org/10.1128/JVI.01579-09 CrossRefPubMed

84.

Mueller SN, Matloubian M, Clemens DM, Sharpe AH, Freeman GJ, Gangappa S, Larsen CP, Ahmed R (2007) Viral targeting of fibroblastic reticular cells contributes to immunosuppression and persistence during chronic infection. Proc Natl Acad Sci U S A 104(39):15430–15435. https://doi.org/10.1073/pnas.0702579104 CrossRefPubMedPubMedCentral

85.

Schacker T (2008) The role of secondary lymphatic tissue in immune deficiency of HIV infection. Aids 22(Suppl 3):S13–S18. https://doi.org/10.1097/01.aids.0000327511.76126.b5 CrossRefPubMed

86.

Zeng M, Smith AJ, Wietgrefe SW, Southern PJ, Schacker TW, Reilly CS, Estes JD, Burton GF, Silvestri G, Lifson JD, Carlis JV, Haase AT (2011) Cumulative mechanisms of lymphoid tissue fibrosis and T cell depletion in HIV-1 and SIV infections. J Clin Invest 121(3):998–1008. https://doi.org/10.1172/JCI45157 CrossRefPubMedPubMedCentral

87.

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(6):652–664. https://doi.org/10.1016/j.chom.2013.05.014 CrossRefPubMedPubMedCentral

88.

Sevilla N, McGavern DB, Teng C, Kunz S, Oldstone MBA (2004) Viral targeting of hematopoietic progenitors and inhibition of DC maturation as a dual strategy for immune subversion. J Clin Invest 113(5):737–745. https://doi.org/10.1172/JCI20243 CrossRefPubMedPubMedCentral

89.

King KY, Goodell MA (2011) Inflammatory modulation of HSCs: viewing the HSC as a foundation for the immune response. Nat Rev Immunol 11(10):685–692. https://doi.org/10.1038/nri3062 CrossRefPubMedPubMedCentral

90.

Goh C, Narayanan S, Hahn YS (2013) Myeloid-derived suppressor cells: the dark knight or the joker in viral infections? Immunol Rev 255(1):210–221. https://doi.org/10.1111/imr.12084 CrossRefPubMedPubMedCentral

91.

Wilson EB, Kidani Y, Elsaesser H, Barnard J, Raff L, Karp CL, Bensinger S, Brooks DG (2012) Emergence of distinct multiarmed immunoregulatory antigen-presenting cells during persistent viral infection. Cell Host Microbe 11(5):481–491. https://doi.org/10.1016/j.chom.2012.03.009 CrossRefPubMedPubMedCentral

92.

Norris BA, Uebelhoer LS, Nakaya HI, Price AA, Grakoui A, Pulendran B (2013) Chronic but not acute virus infection induces sustained expansion of myeloid suppressor cell numbers that inhibit viral-specific T cell immunity. Immunity 38(2):309–321. https://doi.org/10.1016/j.immuni.2012.10.022 CrossRefPubMed

93.

Elsaesser H, Sauer K, Brooks DG (2009) IL-21 is required to control chronic viral infection. Science 324(5934):1569–1572. https://doi.org/10.1126/science.1174182 CrossRefPubMedPubMedCentral

94.

Frohlich A, Kisielow J, Schmitz I, Freigang S, Shamshiev AT, Weber J, Marsland BJ, Oxenius A, Kopf M (2009) IL-21R on T cells is critical for sustained functionality and control of chronic viral infection. Science 324(5934):1576–1580. https://doi.org/10.1126/science.1172815 CrossRefPubMed

95.

Yi JS, Du M, Zajac AJ (2009) A vital role for interleukin-21 in the control of a chronic viral infection. Science 324(5934):1572–1576. https://doi.org/10.1126/science.1175194 CrossRefPubMedPubMedCentral

96.

Williams LD, Bansal A, Sabbaj S, Heath SL, Song W, Tang J, Zajac AJ, Goepfert PA (2011) Interleukin-21-producing HIV-1-specific CD8 T cells are preferentially seen in elite controllers. J Virol 85(5):2316–2324. https://doi.org/10.1128/JVI.01476-10 CrossRefPubMed

97.

Chevalier MF, Julg B, Pyo A, Flanders M, Ranasinghe S, Soghoian DZ, Kwon DS, Rychert J, Lian J, Muller MI, Cutler S, McAndrew E, Jessen H, Pereyra F, Rosenberg ES, Altfeld M, Walker BD, Streeck H (2011) HIV-1-specific interleukin-21+ CD4+ T cell responses contribute to durable viral control through the modulation of HIV-specific CD8+ T cell function. J Virol 85(2):733–741. https://doi.org/10.1128/JVI.02030-10 CrossRefPubMed

98.

Waggoner SN, Cornberg M, Selin LK, Welsh RM (2012) Natural killer cells act as rheostats modulating antiviral T cells. Nature 481(7381):394–398. https://doi.org/10.1038/nature10624 CrossRef

99.

Lang PA, Lang KS, Xu HC, Grusdat M, Parish IA, Recher M, Elford AR, Dhanji S, Shaabani N, Tran CW, Dissanayake D, Rahbar R, Ghazarian M, Brustle A, Fine J, Chen P, Weaver CT, Klose C, Diefenbach A, Haussinger D, Carlyle JR, Kaech SM, Mak TW, Ohashi PS (2012) Natural killer cell activation enhances immune pathology and promotes chronic infection by limiting CD8+ T-cell immunity. Proc Natl Acad Sci U S A 109(4):1210–1215. https://doi.org/10.1073/pnas.1118834109 CrossRefPubMed

100.

Cook KD, Whitmire JK (2013) The depletion of NK cells prevents T cell exhaustion to efficiently control disseminating virus infection. J Immunol 190(2):641–649. https://doi.org/10.4049/jimmunol.1202448 CrossRefPubMed

101.

Belkaid Y, Tarbell K (2009) Regulatory T cells in the control of host-microorganism interactions (*). Annu Rev Immunol 27:551–589. https://doi.org/10.1146/annurev.immunol.021908.132723 CrossRefPubMed

102.

Veiga-Parga T, Sehrawat S, Rouse BT (2013) Role of regulatory T cells during virus infection. Immunol Rev 255(1):182–196. https://doi.org/10.1111/imr.12085 CrossRefPubMedPubMedCentral

103.

Doedens AL, Phan AT, Stradner MH, Fujimoto JK, Nguyen JV, Yang E, Johnson RS, Goldrath AW (2013) Hypoxia-inducible factors enhance the effector responses of CD8(+) T cells to persistent antigen. Nat Immunol 14(11):1173–1182. https://doi.org/10.1038/ni.2714 CrossRefPubMedPubMedCentral

104.

Man K, Gabriel SS, Liao Y, Gloury R, Preston S, Henstridge DC, Pellegrini M, Zehn D, Berberich-Siebelt F, Febbraio MA, Shi W, Kallies A (2017) Transcription factor IRF4 promotes CD8(+) T cell exhaustion and limits the development of memory-like T cells during chronic infection. Immunity 47(6):1129–1141 e1125. https://doi.org/10.1016/j.immuni.2017.11.021 CrossRefPubMed

105.

Utzschneider DT, Charmoy M, Chennupati V, Pousse L, Ferreira DP, Calderon-Copete S, Danilo M, Alfei F, Hofmann M, Wieland D, Pradervand S, Thimme R, Zehn D, Held W (2016) T cell factor 1-expressing memory-like CD8(+) T cells sustain the immune response to chronic viral infections. Immunity 45(2):415–427. https://doi.org/10.1016/j.immuni.2016.07.021 CrossRefPubMed

106.

Im SJ, Hashimoto M, Gerner MY, Lee J, Kissick HT, Burger MC, Shan Q, Hale JS, Lee J, Nasti TH, Sharpe AH, Freeman GJ, Germain RN, Nakaya HI, Xue HH, Ahmed R (2016) Defining CD8+ T cells that provide the proliferative burst after PD-1 therapy. Nature 537(7620):417–421. https://doi.org/10.1038/nature19330 CrossRefPubMedPubMedCentral

107.

Kurachi M, Barnitz RA, Yosef N, Odorizzi PM, DiIorio MA, Lemieux ME, Yates K, Godec J, Klatt MG, Regev A, Wherry EJ, Haining WN (2014) The transcription factor BATF operates as an essential differentiation checkpoint in early effector CD8+ T cells. Nat Immunol 15(4):373–383. https://doi.org/10.1038/ni.2834 CrossRefPubMedPubMedCentral

108.

Intlekofer AM, Takemoto N, Kao C, Banerjee A, Schambach F, Northrop JK, Shen H, Wherry EJ, Reiner SL (2007) Requirement for T-bet in the aberrant differentiation of unhelped memory CD8+ T cells. J Exp Med 204(9):2015–2021. https://doi.org/10.1084/jem.20070841 CrossRefPubMedPubMedCentral

109.

Paley MA, Gordon SM, Bikoff EK, Robertson EJ, Wherry EJ, Reiner SL (2013) Technical advance: fluorescent reporter reveals insights into eomesodermin biology in cytotoxic lymphocytes. J Leukoc Biol 93(2):307–315. https://doi.org/10.1189/jlb.0812400 CrossRefPubMedPubMedCentral

110.

Banerjee A, Gordon SM, Intlekofer AM, Paley MA, Mooney EC, Lindsten T, Wherry EJ, Reiner SL (2010) Cutting edge: the transcription factor eomesodermin enables CD8+ T cells to compete for the memory cell niche. J Immunol 185(9):4988–4992. https://doi.org/10.4049/jimmunol.1002042 CrossRefPubMed

111.

Stelekati E, Chen Z, Manne S, Kurachi M, Ali MA, Lewy K, Cai Z, Nzingha K, McLane LM, Hope JL, Fike AJ, Katsikis PD, Wherry EJ (2018) Long-term persistence of exhausted CD8 T cells in chronic infection is regulated by MicroRNA-155. Cell Rep 23(7):2142–2156. https://doi.org/10.1016/j.celrep.2018.04.038 CrossRefPubMedPubMedCentral

112.

Youngblood B, Noto A, Porichis F, Akondy RS, Ndhlovu ZM, Austin JW, Bordi R, Procopio FA, Miura T, Allen TM, Sidney J, Sette A, Walker BD, Ahmed R, Boss JM, Sekaly RP, Kaufmann DE (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(2):540–544. https://doi.org/10.4049/jimmunol.1203161 CrossRefPubMed

Titel: CD8+ T cell exhaustion
verfasst von: Makoto Kurachi
Publikationsdatum: 15.04.2019
Verlag: Springer Berlin Heidelberg
Erschienen in: Seminars in Immunopathology / Ausgabe 3/2019
Print ISSN: 1863-2297
Elektronische ISSN: 1863-2300
DOI: https://doi.org/10.1007/s00281-019-00744-5

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CD8⁺ T cell exhaustion

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