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

RB Jones, LC Ndhlovu, JD Barbour, PM Sheth… - The Journal of …, 2008 - rupress.org
RB Jones, LC Ndhlovu, JD Barbour, PM Sheth, AR Jha, BR Long, JC Wong, M Satkunarajah…
The Journal of experimental medicine, 2008rupress.org
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 …
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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