T cell exhaustion is a state of T cell dysfunction that arises during many chronic infections and cancer. It is defined by poor effector function, sustained expression of inhibitory receptors and a transcriptional state distinct from that of functional effector or memory T cells. Exhaustion prevents optimal control of infection and tumors. Recently, a clearer picture of the functional and phenotypic profile of exhausted T cells has emerged and T cell exhaustion has been defined in many experimental and clinical settings. Although the pathways involved remain to be fully defined, advances in the molecular delineation of T cell exhaustion are clarifying the underlying causes of this state of differentiation and also suggest promising therapeutic opportunities.
This is a preview of subscription content, access via your institution
Open Access articles citing this article.
Optimizing tumor-associated antigen-stimulated autologous dendritic cell and cytokine-induced killer cell coculture to enhance cytotoxicity for cancer immunotherapy in manufacturing
BMC Immunology Open Access 29 June 2023
Molecular Cancer Open Access 13 June 2023
Use of programmed cell death protein 1 (PD-1) inhibitor therapy in HIV-infected patients with advanced cancer: a single-center study from China
Infectious Agents and Cancer Open Access 30 May 2023
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Rent or buy this article
Prices vary by article type
Prices may be subject to local taxes which are calculated during checkout
Zajac, A.J. et al. Viral immune evasion due to persistence of activated T cells without effector function. J. Exp. Med. 188, 2205–2213 (1998).
Gallimore, A. et al. 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, 1383–1393 (1998).
Virgin, H.W., Wherry, E.J. & Ahmed, R. Redefining chronic viral infection. Cell 138, 30–50 (2009).
Williams, M.A. & Bevan, M.J. Effector and memory CTL differentiation. Annu. Rev. Immunol. 25, 171–192 (2007).
Jameson, S.C. & Masopust, D. Diversity in T cell memory: an embarrassment of riches. Immunity 31, 859–871 (2009).
Wherry, E.J., Blattman, J.N., Murali-Krishna, K., van der Most, R. & Ahmed, R. Viral persistence alters CD8 T-cell immunodominance and tissue distribution and results in distinct stages of functional impairment. J. Virol. 77, 4911–4927 (2003).
Wherry, E.J. & Ahmed, R. Memory CD8 T-cell differentiation during viral infection. J. Virol. 78, 5535–5545 (2004).
Fuller, M.J. & Zajac, A.J. Ablation of CD8 and CD4 T cell responses by high viral loads. J. Immunol. 170, 477–486 (2003).
Moskophidis, D., Lechner, F., Pircher, H. & Zinkernagel, R.M. Virus persistence in acutely infected immunocompetent mice by exhaustion of antiviral cytotoxic effector T cells. Nature 362, 758–761 (1993).
Blattman, J.N., Wherry, E.J., Ha, S.J., van der Most, R.G. & Ahmed, R. Impact of epitope escape on PD-1 expression and CD8 T-cell exhaustion during chronic infection. J. Virol. 83, 4386–4394 (2009).
Brooks, D.G., Teyton, L., Oldstone, M.B. & McGavern, D.B. Intrinsic functional dysregulation of CD4 T cells occurs rapidly following persistent viral infection. J. Virol. 79, 10514–10527 (2005).
Oxenius, A., Zinkernagel, R.M. & Hengartner, H. Comparison of activation versus induction of unresponsiveness of virus-specific CD4+ and CD8+ T cells upon acute versus persistent viral infection. Immunity 9, 449–457 (1998).
Kaufmann, D.E. et al. Upregulation of CTLA-4 by HIV-specific CD4+ T cells correlates with disease progression and defines a reversible immune dysfunction. Nat. Immunol. 8, 1246–1254 (2007).
Urbani, S. et al. Outcome of acute hepatitis C is related to virus-specific CD4 function and maturation of antiviral memory CD8 responses. Hepatology 44, 126–139 (2006).
Frohlich, A. et al. IL-21R on T cells is critical for sustained functionality and control of chronic viral infection. Science 324, 1576–1580 (2009).
Yi, J.S., Du, M. & Zajac, A.J. A vital role for interleukin-21 in the control of a chronic viral infection. Science 324, 1572–1576 (2009).
Elsaesser, H., Sauer, K. & Brooks, D.G. IL-21 is required to control chronic viral infection. Science 324, 1569–1572 (2009).
Blackburn, S.D. & Wherry, E.J. IL-10, T cell exhaustion and viral persistence. Trends Microbiol. 15, 143–146 (2007).
Brooks, D.G. et al. Interleukin-10 determines viral clearance or persistence in vivo. Nat. Med. 12, 1301–1309 (2006).
Betts, M.R. et al. HIV nonprogressors preferentially maintain highly functional HIV-specific CD8+ T cells. Blood 107, 4781–4789 (2006).
Lechner, F. et al. Analysis of successful immune responses in persons infected with hepatitis C virus. J. Exp. Med. 191, 1499–1512 (2000).
Bowen, D.G. & Walker, C.M. Adaptive immune responses in acute and chronic hepatitis C virus infection. Nature 436, 946–952 (2005).
Mueller, S.N. et al. Viral targeting of fibroblastic reticular cells contributes to immunosuppression and persistence during chronic infection. Proc. Natl. Acad. Sci. USA 104, 15430–15435 (2007).
Liu, B., Woltman, A.M., Janssen, H.L. & Boonstra, A. Modulation of dendritic cell function by persistent viruses. J. Leukoc. Biol. 85, 205–214 (2009).
Sevilla, N., Kunz, S., McGavern, D. & Oldstone, M.B. Infection of dendritic cells by lymphocytic choriomeningitis virus. Curr. Top. Microbiol. Immunol. 276, 125–144 (2003).
Matter, M., Odermatt, B., Yagita, H., Nuoffer, J.M. & Ochsenbein, A.F. Elimination of chronic viral infection by blocking CD27 signaling. J. Exp. Med. 203, 2145–2155 (2006).
Schacker, T. The role of secondary lymphatic tissue in immune deficiency of HIV infection. AIDS 22 (Suppl 3), S13–S18 (2008).
Zeng, M. et al. Cumulative mechanisms of lymphoid tissue fibrosis and T cell depletion in HIV-1 and SIV infections. J. Clin. Invest. 121, 998–1008 (2011).
Shin, H. & Wherry, E.J. CD8 T cell dysfunction during chronic viral infection. Curr. Opin. Immunol. 19, 408–415 (2007).
Shin, H., Blackburn, S.D., Blattman, J.N. & Wherry, E.J. Viral antigen and extensive division maintain virus-specific CD8 T cells during chronic infection. J. Exp. Med. 204, 941–949 (2007).
Wherry, E.J., Barber, D.L., Kaech, S.M., Blattman, J.N. & Ahmed, R. Antigen-independent memory CD8 T cells do not develop during chronic viral infection. Proc. Natl. Acad. Sci. USA 101, 16004–16009 (2004).
Migueles, S.A. et al. Defective human immunodeficiency virus-specific CD8+ T-cell polyfunctionality, proliferation, and cytotoxicity are not restored by antiretroviral therapy. J. Virol. 83, 11876–11889 (2009).
Kasprowicz, V. et al. Hepatitis C virus (HCV) sequence variation induces an HCV-specific T-cell phenotype analogous to spontaneous resolution. J. Virol. 84, 1656–1663 (2010).
Streeck, H. et al. Antigen load and viral sequence diversification determine the functional profile of HIV-1-specific CD8+ T cells. PLoS Med. 5, e100 (2008).
Vezys, V. et al. Continuous recruitment of naïve T cells contributes to heterogeneity of antiviral CD8 T cells during persistent infection. J. Exp. Med. 10, 2263–2269 (2006).
Miller, N.E., Bonczyk, J.R., Nakayama, Y. & Suresh, M. Role of thymic output in regulating CD8 T-cell homeostasis during acute and chronic viral infection. J. Virol. 79, 9419–9429 (2005).
Trimble, L.A., Kam, L.W., Friedman, R.S., Xu, Z. & Lieberman, J. CD3zeta and CD28 down-modulation on CD8 T cells during viral infection. Blood 96, 1021–1029 (2000).
Reignat, S. et al. Escaping high viral load exhaustion: CD8 cells with altered tetramer binding in chronic hepatitis B virus infection. J. Exp. Med. 195, 1089–1101 (2002).
Freeman, G.J., Wherry, E.J., Ahmed, R. & Sharpe, A.H. Reinvigorating exhausted HIV-specific T cells via PD-1-PD-1 ligand blockade. J. Exp. Med. 203, 2223–2227 (2006).
Barber, D.L. et al. Restoring function in exhausted CD8 T cells during chronic viral infection. Nature 439, 682–687 (2006).
Petrovas, C. et al. PD-1 is a regulator of virus-specific CD8+ T cell survival in HIV infection. J. Exp. Med. 203, 2281–2292 (2006).
Trautmann, L. et al. Upregulation of PD-1 expression on HIV-specific CD8+ T cells leads to reversible immune dysfunction. Nat. Med. 12, 1198–1202 (2006).
Day, C.L. et al. PD-1 expression on HIV-specific T cells is associated with T-cell exhaustion and disease progression. Nature 443, 350–354 (2006).
Velu, V. et al. Enhancing SIV-specific immunity in vivo by PD-1 blockade. Nature 458, 206–210 (2009).
Brahmer, J.R. et al. Phase I study of single-agent anti-programmed death-1 (MDX-1106) in refractory solid tumors: safety, clinical activity, pharmacodynamics, and immunologic correlates. J. Clin. Oncol. 28, 3167–3175 (2010).
Blackburn, S.D. et al. Coregulation of CD8+ T cell exhaustion by multiple inhibitory receptors during chronic viral infection. Nat. Immunol. 10, 29–37 (2009).
Crawford, A. & Wherry, E.J. The diversity of costimulatory and inhibitory receptor pathways and the regulation of antiviral T cell responses. Curr. Opin. Immunol. 21, 179–186 (2009).
Nakamoto, N. et al. Synergistic reversal of intrahepatic HCV-specific CD8 T cell exhaustion by combined PD-1/CTLA-4 blockade. PLoS Pathog. 5, e1000313 (2009).
Jin, H.T. et al. Cooperation of Tim-3 and PD-1 in CD8 T-cell exhaustion during chronic viral infection. Proc. Natl. Acad. Sci. USA 107, 14733–14738 (2010).
Kassu, A. et al. Regulation of virus-specific CD4+ T cell function by multiple costimulatory receptors during chronic HIV infection. J. Immunol. 185, 3007–3018 (2010).
Grosso, J.F. et al. Functionally distinct LAG-3 and PD-1 subsets on activated and chronically stimulated CD8 T cells. J. Immunol. 182, 6659–6669 (2009).
Matsuzaki, J. et al. 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. USA 107, 7875–7880 (2010).
Fourcade, J. et al. 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, 2175–2186 (2010).
Sakuishi, K. et al. Targeting Tim-3 and PD-1 pathways to reverse T cell exhaustion and restore anti-tumor immunity. J. Exp. Med. 207, 2187–2194 (2010).
Petrovas, C. et al. SIV-specific CD8+ T cells express high levels of PD1 and cytokines but have impaired proliferative capacity in acute and chronic SIVmac251 infection. Blood 110, 928–936 (2007).
Blackburn, S.D. et al. Tissue specific differences in PD-1 and PD-L1 expression during chronic viral infection: implications for CD8 T cell exhaustion. J. Virol. 84, 2078–2089 (2010).
Blackburn, S.D., Shin, H., Freeman, G.J. & Wherry, E.J. Selective expansion of a subset of exhausted CD8 T cells by αPD-L1 blockade. Proc. Natl. Acad. Sci. USA 105, 15016–15021 (2008).
Workman, C.J. et al. Lymphocyte activation gene-3 (CD223) regulates the size of the expanding T cell population following antigen activation in vivo. J. Immunol. 172, 5450–5455 (2004).
Pentcheva-Hoang, T., Egen, J.G., Wojnoonski, K. & Allison, J.P. B7-1 and B7-2 selectively recruit CTLA-4 and CD28 to the immunological synapse. Immunity 21, 401–413 (2004).
Okazaki, T., Maeda, A., Nishimura, H., Kurosaki, T. & Honjo, T. PD-1 immunoreceptor inhibits B cell receptor-mediated signaling by recruiting src homology 2-domain-containing tyrosine phosphatase 2 to phosphotyrosine. Proc. Natl. Acad. Sci. USA 98, 13866–13871 (2001).
Chemnitz, J.M., Parry, R.V., Nichols, K.E., June, C.H. & Riley, J.L. 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, 945–954 (2004).
Parry, R.V. et al. CTLA-4 and PD-1 receptors inhibit T-cell activation by distinct mechanisms. Mol. Cell. Biol. 25, 9543–9553 (2005).
Quigley, M. et al. Transcriptional analysis of HIV-specific CD8+ T cells shows that PD-1 inhibits T cell function by upregulating BATF. Nat. Med. 16, 1147–1151 (2010).
Zhou, S., Ou, R., Huang, L. & Moskophidis, D. Critical role for perforin-, Fas/FasL-, and TNFR1-mediated cytotoxic pathways in down-regulation of antigen-specific T cells during persistent viral infection. J. Virol. 76, 829–840 (2002).
Bucks, C.M., Norton, J.A., Boesteanu, A.C., Mueller, Y.M. & Katsikis, P.D. Chronic antigen stimulation alone is sufficient to drive CD8+ T cell exhaustion. J. Immunol. 182, 6697–6708 (2009).
Ejrnaes, M. et al. Resolution of a chronic viral infection after interleukin-10 receptor blockade. J. Exp. Med. 203, 2461–2472 (2006).
Said, E.A. et al. Programmed death-1-induced interleukin-10 production by monocytes impairs CD4+ T cell activation during HIV infection. Nat. Med. 16, 452–459 (2011).
Tinoco, R., Alcalde, V., Yang, Y., Sauer, K. & Zuniga, E.I. Cell-intrinsic transforming growth factor-β signaling mediates virus-specific CD8+ T cell deletion and viral persistence in vivo. Immunity 31, 145–157 (2009).
Alatrakchi, N. et al. Hepatitis C virus (HCV)-specific CD8+ cells produce transforming growth factor β that can suppress HCV-specific T-cell responses. J. Virol. 81, 5882–5892 (2007).
Garba, M.L., Pilcher, C.D., Bingham, A.L., Eron, J. & Frelinger, J.A. HIV antigens can induce TGF-β(1)-producing immunoregulatory CD8+ T cells. J. Immunol. 168, 2247–2254 (2002).
Leone, A., Picker, L.J. & Sodora, D.L. IL-2, IL-7 and IL-15 as immuno-modulators during SIV/HIV vaccination and treatment. Curr. HIV Res. 7, 83–90 (2009).
Blattman, J.N. et al. Therapeutic use of IL-2 to enhance antiviral T-cell responses in vivo. Nat. Med. 9, 540–547 (2003).
Pellegrini, M. et al. IL-7 engages multiple mechanisms to overcome chronic viral infection and limit organ pathology. Cell 144, 601–613 (2011).
Nanjappa, S.G., Kim, E.H. & Suresh, M. Immunotherapeutic effects of IL-7 during a chronic viral infection in mice. Blood published online, doi:10.1182/blood-2010-12-323154 (23 March 2011).
Yue, F.Y. et al. HIV-specific IL-21 producing CD4+ T cells are induced in acute and chronic progressive HIV infection and are associated with relative viral control. J. Immunol. 185, 498–506 (2011).
Chevalier, M.F. et al. 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, 733–741 (2011).
Williams, L.D. et al. Interleukin-21-producing HIV-1-specific CD8 T cells are preferentially seen in elite controllers. J. Virol. 85, 2316–2324 (2011).
Punkosdy, G.A. et al. Regulatory T-cell expansion during chronic viral infection is dependent on endogenous retroviral superantigens. Proc. Natl. Acad. Sci. USA 108, 3677–3682 (2011).
Belkaid, Y. & Rouse, B.T. Natural regulatory T cells in infectious disease. Nat. Immunol. 6, 353–360 (2005).
Collison, L.W. et al. The inhibitory cytokine IL-35 contributes to regulatory T-cell function. Nature 450, 566–569 (2007).
Collison, L.W. et al. IL-35-mediated induction of a potent regulatory T cell population. Nat. Immunol. 11, 1093–1101 (2011).
Rifa'i, M., Kawamoto, Y., Nakashima, I. & Suzuki, H. Essential roles of CD8+CD122+ regulatory T cells in the maintenance of T cell homeostasis. J. Exp. Med. 200, 1123–1134 (2004).
Joosten, S.A. et al. Identification of a human CD8+ regulatory T cell subset that mediates suppression through the chemokine CC chemokine ligand 4. Proc. Natl. Acad. Sci. USA 104, 8029–8034 (2007).
Martinez, F.O., Helming, L. & Gordon, S. Alternative activation of macrophages: an immunologic functional perspective. Annu. Rev. Immunol. 27, 451–483 (2009).
Mellor, A.L. & Munn, D.H. IDO expression by dendritic cells: tolerance and tryptophan catabolism. Nat. Rev. Immunol. 4, 762–774 (2004).
Haining, W.N. & Wherry, E.J. Integrating genomic signatures for immunologic discovery. Immunity 32, 152–161 (2010).
Wherry, E.J. et al. Molecular signature of CD8+ T cell exhaustion during chronic viral infection. Immunity 27, 670–684 (2007).
Shin, H. et al. A role for the transcriptional repressor Blimp-1 in CD8+ T cell exhaustion during chronic viral infection. Immunity 31, 309–320 (2009).
Martins, G. & Calame, K. Regulation and functions of Blimp-1 in T and B lymphocytes. Annu. Rev. Immunol. 26, 133–169 (2008).
Bikoff, E.K., Morgan, M.A. & Robertson, E.J. An expanding job description for Blimp-1/PRDM1. Curr. Opin. Genet. Dev. 19, 379–385 (2009).
Kallies, A., Xin, A., Belz, G.T. & Nutt, S.L. Blimp-1 transcription factor is required for the differentiation of effector CD8+ T cells and memory responses. Immunity 31, 283–295 (2009).
Rutishauser, R.L. et al. Transcriptional repressor Blimp-1 promotes CD8+ T cell terminal differentiation and represses the acquisition of central memory T cell properties. Immunity 31, 296–308 (2009).
Joshi, N.S. & Kaech, S.M. Effector CD8 T cell development: a balancing act between memory cell potential and terminal differentiation. J. Immunol. 180, 1309–1315 (2008).
Kao, C. et al. T-bet represses expression of PD-1 and sustains virus-specific CD8 T cell responses during chronic infection. Nat. Immunol. (in the press).
Macian, F. et al. Transcriptional mechanisms underlying lymphocyte tolerance. Cell 109, 719–731 (2002).
Agnellini, P. et al. Impaired NFAT nuclear translocation results in split exhaustion of virus-specific CD8+ T cell functions during chronic viral infection. Proc. Natl. Acad. Sci. USA 104, 4565–4570 (2007).
Migueles, S.A. et al. Lytic granule loading of CD8+ T cells is required for HIV-infected cell elimination associated with immune control. Immunity 29, 1009–1021 (2008).
Oestreich, K.J., Yoon, H., Ahmed, R. & Boss, J.M. NFATc1 regulates PD-1 expression upon T cell activation. J. Immunol. 181, 4832–4839 (2008).
Avni, O. et al. TH cell differentiation is accompanied by dynamic changes in histone acetylation of cytokine genes. Nat. Immunol. 3, 643–651 (2002).
Mehta, D.S., Wurster, A.L., Weinmann, A.S. & Grusby, M.J. NFATc2 and T-bet contribute to T-helper-cell-subset-specific regulation of IL-21 expression. Proc. Natl. Acad. Sci. USA 102, 2016–2021 (2005).
Williams, K.L. et al. Characterization of murine BATF: a negative regulator of activator protein-1 activity in the thymus. Eur. J. Immunol. 31, 1620–1627 (2001).
Schraml, B.U. et al. The AP-1 transcription factor Batf controls TH17 differentiation. Nature 460, 405–409 (2009).
Schwartz, R.H. T cell anergy. Annu. Rev. Immunol. 21, 305–334 (2003).
Brenchley, J.M. et al. Expression of CD57 defines replicative senescence and antigen-induced apoptotic death of CD8+ T cells. Blood 101, 2711–2720 (2003).
van Leeuwen, E.M., de Bree, G.J., ten Berge, I.J. & van Lier, R.A. Human virus-specific CD8+ T cells: diversity specialists. Immunol. Rev. 211, 225–235 (2006).
Lichterfeld, M. et al. Telomerase activity of HIV-1-specific CD8+ T cells: constitutive up-regulation in controllers and selective increase by blockade of PD ligand 1 in progressors. Blood 112, 3679–3687 (2008).
Akbar, A.N. & Henson, S.M. Are senescence and exhaustion intertwined or unrelated processes that compromise immunity? Nat. Rev. Immunol. 11, 289–295 (2011).
Wirth, T.C. et al. Repetitive antigen stimulation induces stepwise transcriptome diversification but preserves a core signature of memory CD8+ T cell differentiation. Immunity 33, 128–140 (2011).
Hertoghs, K.M. et al. Molecular profiling of cytomegalovirus-induced human CD8+ T cell differentiation. J. Clin. Invest. 120, 4077–4090 (2011).
Brooks, D.G., Lee, A.M., Elsaesser, H., McGavern, D.B. & Oldstone, M.B. IL-10 blockade facilitates DNA vaccine-induced T cell responses and enhances clearance of persistent virus infection. J. Exp. Med. 205, 533–541 (2008).
Brooks, D.G. et al. IL-10 and PD-L1 operate through distinct pathways to suppress T-cell activity during persistent viral infection. Proc. Natl. Acad. Sci. USA 105, 20428–20433 (2008).
Ha, S.J. et al. Enhancing therapeutic vaccination by blocking PD-1-mediated inhibitory signals during chronic infection. J. Exp. Med. 205, 543–555 (2008).
Nakamoto, N. et al. Functional restoration of HCV-specific CD8 T cells by PD-1 blockade is defined by PD-1 expression and compartmentalization. Gastroenterology 134, 1927–1937 (2008).
Lauer, G.M. & Kim, A.Y. Spontaneous resolution of chronic hepatitis C virus infection: are we missing something? Clin. Infect. Dis. 42, 953–954 (2006).
Moir, S. et al. Evidence for HIV-associated B cell exhaustion in a dysfunctional memory B cell compartment in HIV-infected viremic individuals. J. Exp. Med. 205, 1797–1805 (2008).
Weiss, G.E. et al. Atypical memory B cells are greatly expanded in individuals living in a malaria-endemic area. J. Immunol. 183, 2176–2182 (2009).
I thank the members of my laboratory and N. Haining for discussions. Supported by the US National Institutes of Health (AI071309, AI083022, AI082630, HHSN226200500030), the Commonwealth of Pennsylvania, the Ellison Medical Foundation and the Dana Foundation.
E.J.W. has a patent licensing agreement for the PD-1 pathway.
About this article
Cite this article
Wherry, E. T cell exhaustion. Nat Immunol 12, 492–499 (2011). https://doi.org/10.1038/ni.2035
This article is cited by
Immunity & Ageing (2023)
Optimizing tumor-associated antigen-stimulated autologous dendritic cell and cytokine-induced killer cell coculture to enhance cytotoxicity for cancer immunotherapy in manufacturing
BMC Immunology (2023)
Journal of Translational Medicine (2023)
Molecular Cancer (2023)
ScRNA-seq revealed an immunosuppression state and tumor microenvironment heterogeneity related to lymph node metastasis in prostate cancer
Experimental Hematology & Oncology (2023)