Tim-3 Expression Defines a Novel Population of Dysfunctional T Cells with Highly Elevated Frequencies in Progressive HIV-1 Infection

Overview

Journal J Exp Med

Specialties Allergy & Immunology
General Medicine

Date 2008 Nov 13

PMID 19001139

Citations 439

Authors

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 Spotts

Frederick M Hecht

Tae-Wook Chun

Joseph M McCune

Rupert Kaul

James M Rini

Douglas F Nixon

Mario A Ostrowski

Affiliations

Soon will be listed here.

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.

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