T cell exhaustion

Nature Immunology

Volumn 12, Issue 6, 2011, Pages 492-499

  Wherry, E John ^a  

^a UNIVERSITY OF PENNSYLVANIA   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

CLONAL ANERGY; EFFECTOR CELL; LYMPHOCYTE DIFFERENTIATION; MEMORY T LYMPHOCYTE; PRIORITY JOURNAL; REVIEW; T LYMPHOCYTE;

ANIMALS; BACTERIAL INFECTIONS; CD8-POSITIVE T-LYMPHOCYTES; CYTOKINES; HUMANS; IMMUNOLOGIC MEMORY; INFLAMMATION MEDIATORS; MODELS, IMMUNOLOGICAL; T-LYMPHOCYTES; VIRUS DISEASES;

EID: 79956077563     PISSN: 15292908     EISSN: 15292916     Source Type: Journal    
DOI: 10.1038/ni.2035     Document Type: Review

References (116)

1. 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). (Pubitemid 29028493)
2. 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). (Pubitemid 28215398)
3. Virgin, H.W., Wherry, E.J. & Ahmed, R. Redefining chronic viral infection. Cell 138, 30-50 (2009).
4. Williams, M.A. & Bevan, M.J. Effector and memory CTL differentiation. Annu. Rev. Immunol. 25, 171-192 (2007). (Pubitemid 46697906)
5. Jameson, S.C. & Masopust, D. Diversity in T cell memory: an embarrassment of riches. Immunity 31, 859-871 (2009).
6. 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). (Pubitemid 36402840)
7. Wherry, E.J. & Ahmed, R. Memory CD8 T-cell differentiation during viral infection. J. Virol. 78, 5535-5545 (2004). (Pubitemid 38661640)
8. Fuller, M.J. & Zajac, A.J. Ablation of CD8 and CD4 T cell responses by high viral loads. J. Immunol. 170, 477-486 (2003). (Pubitemid 36026174)
9. 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). (Pubitemid 23125981)
10. 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).
11. 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). (Pubitemid 41098591)
12. 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). (Pubitemid 28499196)
13. 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). (Pubitemid 350011764)
14. 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). (Pubitemid 44049146)
15. 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).
16. 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).
17. Elsaesser, H., Sauer, K. & Brooks, D.G. IL-21 is required to control chronic viral infection. Science 324, 1569-1572 (2009).
18. Blackburn, S.D. & Wherry, E.J. IL-10, T cell exhaustion and viral persistence. Trends Microbiol. 15, 143-146 (2007). (Pubitemid 46528253)
19. Brooks, D.G. et al. Interleukin-10 determines viral clearance or persistence in vivo. Nat. Med. 12, 1301-1309 (2006). (Pubitemid 44706933)
20. Betts, M.R. et al. HIV nonprogressors preferentially maintain highly functional HIV-specific CD8+ T cells. Blood 107, 4781-4789 (2006). (Pubitemid 43882629)
21. Lechner, F. et al. Analysis of successful immune responses in persons infected with hepatitis C virus. J. Exp. Med. 191, 1499-1512 (2000). (Pubitemid 30257347)
22. Bowen, D.G. & Walker, C.M. Adaptive immune responses in acute and chronic hepatitis C virus infection. Nature 436, 946-952 (2005). (Pubitemid 41191670)
23. Mueller, S.N. et al. Viral targeting of fibroblastic reticular cells contributes to immunosuppression and persistence during chronic infection. Proc. Natl. Acad. Sci. USA104, 15430-15435 (2007). (Pubitemid 47502934)
24. 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).
25. 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). (Pubitemid 36538350)
26. 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). (Pubitemid 44352235)
27. Schacker, T. The role of secondary lymphatic tissue in immune deficiency of HIV infection. AIDS 22 (Suppl 3), S13-S18 (2008).
28. 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).
29. Shin, H. & Wherry, E.J. CD8 T cell dysfunction during chronic viral infection. Curr. Opin. Immunol. 19, 408-415 (2007). (Pubitemid 47284857)
30. 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). (Pubitemid 46631621)
31. 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. USA101, 16004-16009 (2004). (Pubitemid 39507917)
32. 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).
33. 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).
34. 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).
35. 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). (Pubitemid 44498361)
36. 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). (Pubitemid 41022286)
37. 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). (Pubitemid 30616869)
38. 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). (Pubitemid 34517136)
39. 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). (Pubitemid 44498355)
40. Barber, D.L. et al. Restoring function in exhausted CD8 T cells during chronic viral infection. Nature 439, 682-687 (2006). (Pubitemid 43237609)
41. 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). (Pubitemid 44498363)
42. 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). (Pubitemid 44527357)
43. 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). (Pubitemid 44435155)
44. Velu, V. et al. Enhancing SIV-specific immunity in vivo by PD-1 blockade. Nature 458, 206-210 (2009).
45. 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).
46. 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).
47. 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).
48. 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).
49. 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. USA107, 14733-14738 (2010).
50. 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).
51. 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).
52. 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. USA107, 7875-7880 (2010).
53. 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).
54. 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).
55. 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). (Pubitemid 47267431)
56. 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).
57. 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. USA105, 15016-15021 (2008).
58. 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). (Pubitemid 38542045)
59. 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). (Pubitemid 39208341)
60. 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. USA98, 13866-13871 (2001). (Pubitemid 33115990)
61. 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). (Pubitemid 38924267)
62. 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). (Pubitemid 41507854)
63. 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).
64. 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). (Pubitemid 34033380)
65. 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).
66. Ejrnaes, M. et al. Resolution of a chronic viral infection after interleukin-10 receptor blockade. J. Exp. Med. 203, 2461-2472 (2006). (Pubitemid 44664616)
67. 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).
68. 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).
69. 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). (Pubitemid 46847025)
70. 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). (Pubitemid 34173033)
71. 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).
72. Blattman, J.N. et al. Therapeutic use of IL-2 to enhance antiviral T-cell responses in vivo. Nat. Med. 9, 540-547 (2003). (Pubitemid 36597099)
73. Pellegrini, M. et al. IL-7 engages multiple mechanisms to overcome chronic viral infection and limit organ pathology. Cell 144, 601-613 (2011).
74. 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).
75. 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).
76. 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).
77. 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).
78. Punkosdy, G.A. et al. Regulatory T-cell expansion during chronic viral infection is dependent on endogenous retroviral superantigens. Proc. Natl. Acad. Sci. USA108, 3677-3682 (2011).
79. Belkaid, Y. & Rouse, B.T. Natural regulatory T cells in infectious disease. Nat. Immunol. 6, 353-360 (2005). (Pubitemid 41716772)
80. Collison, L.W. et al. The inhibitory cytokine IL-35 contributes to regulatory T-cell function. Nature 450, 566-569 (2007). (Pubitemid 350190247)
81. Collison, L.W. et al. IL-35-mediated induction of a potent regulatory T cell population. Nat. Immunol. 11, 1093-1101 (2011).
82. 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). (Pubitemid 39507052)
83. 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. USA104, 8029-8034 (2007). (Pubitemid 47185870)
84. Martinez, F.O., Helming, L. & Gordon, S. Alternative activation of macrophages: an immunologic functional perspective. Annu. Rev. Immunol. 27, 451-483 (2009).
85. Mellor, A.L. & Munn, D.H. IDO expression by dendritic cells: tolerance and tryptophan catabolism. Nat. Rev. Immunol. 4, 762-774 (2004). (Pubitemid 39336293)
86. Haining, W.N. & Wherry, E.J. Integrating genomic signatures for immunologic discovery. Immunity 32, 152-161 (2010).
87. Wherry, E.J. et al. Molecular signature of CD8+ T cell exhaustion during chronic viral infection. Immunity 27, 670-684 (2007). (Pubitemid 47615511)
88. 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).
89. Martins, G. & Calame, K. Regulation and functions of Blimp-1 in T and B lymphocytes. Annu. Rev. Immunol. 26, 133-169 (2008). (Pubitemid 351600373)
90. 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).
91. 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).
92. 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).
93. 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).
94. 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).
95. Macian, F. et al. Transcriptional mechanisms underlying lymphocyte tolerance. Cell 109, 719-731 (2002).
96. 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. USA104, 4565-4570 (2007). (Pubitemid 47186265)
97. 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).
98. 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).
99. Avni, O. et al. TH cell differentiation is accompanied by dynamic changes in histone acetylation of cytokine genes. Nat. Immunol. 3, 643-651 (2002). (Pubitemid 34752473)
100. 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. USA102, 2016-2021 (2005). (Pubitemid 40262004)
101. 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). (Pubitemid 32454711)
102. Schraml, B.U. et al. The AP-1 transcription factor Batf controls TH17 differentiation. Nature 460, 405-409 (2009).
103. Schwartz, R.H. T cell anergy. Annu. Rev. Immunol. 21, 305-334 (2003). (Pubitemid 37174534)
104. 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). (Pubitemid 36857634)
105. 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). (Pubitemid 43882975)
106. 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).
107. Akbar, A.N. & Henson, S.M. Are senescence and exhaustion intertwined or unrelated processes that compromise immunity? Nat. Rev. Immunol. 11, 289-295 (2011).
108. 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).
109. Hertoghs, K.M. et al. Molecular profiling of cytomegalovirus-induced human CD8+ T cell differentiation. J. Clin. Invest. 120, 4077-4090 (2011).
110. 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). (Pubitemid 351439301)
111. 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. USA105, 20428-20433 (2008).
112. 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).
113. 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).
114. 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).
115. 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).
116. 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).