Journal
JOURNAL OF EXPERIMENTAL MEDICINE
Volume 205, Issue 12, Pages 2763-2779Publisher
ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.20081398
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Funding
- Canadian Institutes for Health Research (CIHR)
- UCSF Gladstone Institute of Virology & Immunology Center for AIDS Research [P30 AI027763]
- UCSF AIDS Biology Program of the AIDS Research Institute (ARI)
- National Institutes of Health [AI60379, AI68498, AI64520, AI066917, U01 AI43641]
- Irvington Institute/Dana Foundation
- University- wide AIDS Research Program [F05-GI-219]
- Burroughs Wellcome Fund Clinical Scientist Award in Translational Research
- National Institutes of Health Roadmap for Medical Research [DPI OD00329]
- Canada Research Chair Program
- CIHR Operating [HOP-81735]
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Progressive loss of T cell functionality is a hallmark of chronic infection with human immunodeficiency virus 1 (HIV-1). We have identified a novel population of dysfunctional T cells marked by surface expression of the glycoprotein Tim-3. The frequency of this population was increased in HIV-1-infected individuals to a mean of 49.4 +/- SD 12.9% of CD8(+) T cells expressing Tim-3 in HIV-1-infected chronic progressors versus 28.5 +/- 6.8% in HIV-1-uninfected individuals. Levels of Tim-3 expression on T cells from HIV-1-infected inviduals correlated positively with HIV-1 viral load and CD38 expression and inversely with CD4(+) T cell count. In progressive HIV-1 infection, Tim-3 expression was up-regulated on HIV-1 specific CD8(+) T cells. Tim-3-expressing T cells failed to produce cytokine or proliferate in response to antigen and exhibited impaired Stat5, Erk1/2, and p38 signaling. Blocking the Tim-3 signaling pathway restored proliferation and enhanced cytokine production in HIV-1-specifi c T cells. Thus, Tim-3 represents a novel target for the therapeutic reversal of HIV-1-associated T cell dysfunction.
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