Cooperation of Tim-3 and PD-1 in CD8 T-cell exhaustion during chronic viral infection

Hyun Tak Jin, Ana C. Anderson, Wendy G. Tan, Erin E. West, Sang-Jun Ha, Koichi Araki, Gordon J. Freeman, Vijay K. Kuchroo, Rafi Ahmed

Research output: Contribution to journalArticle

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Abstract

Inhibitory receptors play a crucial role in regulating CD8 T-cell function during chronic viral infection. T-cell Ig- and mucin-domain-containing molecule-3 (Tim-3) is well known to negatively regulate T-cell responses, but its role in CD8 T-cell exhaustion during chronic infection in vivo remains unclear. In this study, we document coregulation of CD8 T cell exhaustion by Tim-3 and PD-1 during chronic lymphocytic choriomeningitis virus infection. Whereas Tim-3 was only transiently expressed by CD8 T cells after acute infection, virus-specific CD8 T cells retained high Tim-3 expression throughout chronic infection. The majority (approximately 65% to 80%) of lymphocytic choriomeningitis virus-specific CD8 T cells in lymphoid and nonlymphoid organs coexpressedTim-3andPD-1. This coexpression of Tim-3 and PD-1 was associated with more severe CD8 T-cell exhaustion in terms of proliferation and secretion of effector cytokines such as IFN-γ, TNF-α, and IL-2. Interestingly, CD8 T cells expressing both inhibitory receptors also produced the suppressive cytokine IL-10. Most importantly, combined blockade of Tim-3 and PD-1 pathways in vivo synergistically improved CD8 T cell responses and viral control in chronically infected mice. Taken together, our study defines a parameter for determining the severity of CD8 T cell dysfunction and for identifying virus-specific CD8 T cells that produce IL-10, and shows that targeting both PD-1 and Tim-3 is an effective immune strategy for treating chronic viral infections.

Original languageEnglish
Pages (from-to)14733-14738
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume107
Issue number33
DOIs
Publication statusPublished - 2010 Aug 17

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Virus Diseases
T-Lymphocytes
Lymphocytic choriomeningitis virus
Interleukin-10
Cytokines
Mucins
Infection
Interleukin-2

All Science Journal Classification (ASJC) codes

  • General

Cite this

Jin, Hyun Tak ; Anderson, Ana C. ; Tan, Wendy G. ; West, Erin E. ; Ha, Sang-Jun ; Araki, Koichi ; Freeman, Gordon J. ; Kuchroo, Vijay K. ; Ahmed, Rafi. / Cooperation of Tim-3 and PD-1 in CD8 T-cell exhaustion during chronic viral infection. In: Proceedings of the National Academy of Sciences of the United States of America. 2010 ; Vol. 107, No. 33. pp. 14733-14738.
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Cooperation of Tim-3 and PD-1 in CD8 T-cell exhaustion during chronic viral infection. / Jin, Hyun Tak; Anderson, Ana C.; Tan, Wendy G.; West, Erin E.; Ha, Sang-Jun; Araki, Koichi; Freeman, Gordon J.; Kuchroo, Vijay K.; Ahmed, Rafi.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 107, No. 33, 17.08.2010, p. 14733-14738.

Research output: Contribution to journalArticle

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AU - Jin, Hyun Tak

AU - Anderson, Ana C.

AU - Tan, Wendy G.

AU - West, Erin E.

AU - Ha, Sang-Jun

AU - Araki, Koichi

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