期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 107, 期 33, 页码 14733-14738出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1009731107
关键词
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资金
- Gates Foundation Grand Challenge in Global Health
- National Institutes of Health [AI054456, AI08080192, AI056299, AI73748, NS038037, NS045937, NS030843, NS054096]
- Ministry for Health, Welfare and Family Affairs, Republic of Korea [A091204]
- National Multiple Sclerosis Society
- Juvenile Diabetes Research Foundation Center for Immunological Tolerance at Harvard University
- Ragon Institute of Massachusetts Institute of Technology
- Massachusetts General Hospital
- Harvard University
- National Institutes of Health
- Korea Health Promotion Institute [A091204] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
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 coexpressed Tim-3 and PD-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-gamma, TNF-alpha, 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.
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