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

By R. B. Jones, L. Ndhlovu, Jason D. Barbour, P. Sheth, A. Jha, B. Long, Jessica Wong, Malathy Satkunarajah, Marc Schweneker, J. M. Chapman and 17 more. Journal of Experimental Medicine, 2008

797 citations recorded by the source corpus.

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.

Subfields: Immunology, Virology

View Paper: https://www.semanticscholar.org/paper/10c6c16fd27c46ba421b6bb692cab2a1a139d078

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In Immunology

1. G. Freeman
2. V. Kuchroo
3. A. Anderson
4. Rafi Ahmed
5. K. Araki
6. J. Snyder-Cappione
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8. B. Blazar

In Virology

1. Rafi Ahmed
2. K. Araki

Citations in the corpus

• TIM genes: a family of cell surface phosphatidylserine receptors that regulate innate and adaptive immunity (2010, background): “Two recent studies have implicated TIM-3 in mediating T-cell dysfunction associated with chronic viral infections (83, 84).”
• Multivariate Computational Analysis of Gamma Delta T Cell Inhibitory Receptor Signatures Reveals the Divergence of Healthy and ART-Suppressed HIV+ Aging (2018, result): “While increased IR expression on T cell populations has been reported with aging in mice and humans [52-56], and separately with HIV infection [49, 57-59], a more comprehensive investigation of IR signatures on circulating immune cells from matched younger and older subjects with and without ART-sup”
• Expanding roles for CD4+ T cells in immunity to viruses (2012, background): “122 ), block T cell immunoglobulin domain and mucin domain protein 3 (TIM3”
• Upregulation of Tim-3 and PD-1 expression is associated with tumor antigen–specific CD8+ T cell dysfunction in melanoma patients (2010, background): “Recently, Tim-3 up-regulation has been reported in HIV-specific and HCV-specific CD8+ T cells in patients with progressive HIV infection and chronic hepatitis C, respectively (Jones et al., 2008; Golden-Mason et al., 2009).”
• Targeting Tim-3 and PD-1 pathways to reverse T cell exhaustion and restore anti-tumor immunity (2010, background): “Our observations, along with the previous demonstrations that blockade of either the PD-1 or Tim-3 (Jones et al., 2008; Golden-Mason et al., 2009) signaling pathways can improve T cell function in the context of chronic infections, raised the possibility that combined targeting of these two…”
• Cooperation of Tim-3 and PD-1 in CD8 T-cell exhaustion during chronic viral infection (2010, background): “Recently, it was reported that Tim-3 was expressed by virus-specific T cells during HIV-1 and HCV infections, and the expression levels correlated with the state of CD8 T-cell exhaustion (12, 13).”