Tim-3 expression defines a novel population of dysfunctional T cells with highly elevated frequencies in progressive HIV-1 infection

R. Brad Jones, Lishomwa C. Ndhlovu, Jason D. Barbour, Prameet M. Sheth, Aashish R. Jha, Brian R. Long, Jessica C. Wong, Malathy Satkunarajah, Marc Schweneker, Joan M. Chapman, Gabor Gyenes, Bahareh Vali, Martin D. Hyrcza, Feng Yun Yue, Colin Kovacs, Aref Sassi, Mona Loutfy, Roberta Halpenny, Desmond Persad, Gerald SpottsFrederick M. Hecht, Tae Wook Chun, Joseph M. McCune, Rupert Kaul, James M. Rini, Douglas F. Nixon, Mario A. Ostrowski

Research output: Contribution to journalArticle

Abstract

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-specific T cells. Thus, Tim-3 represents a novel target for the therapeutic reversal of HIV-1-associated T cell dysfunction.

Original languageEnglish (US)
Pages (from-to)2763-2779
Number of pages17
JournalJournal of Experimental Medicine
Volume205
Issue number12
DOIs
StatePublished - Nov 12 2008

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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