Article

Cooperation of Tim-3 and PD-1 in CD8 T-cell exhaustion during chronic viral infection

Department of Microbiology and Immunology, Emory University School of Medicine, Emory Vaccine Center, Atlanta, GA 30322, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.81). 08/2010; 107(33):14733-8. DOI: 10.1073/pnas.1009731107
Source: PubMed

ABSTRACT Inhibitory receptors play a crucial role in regulating CD8 T-cell function during chronic viral infection. T-cell Ig- and mucin-domain-containing molecule-3 (Tim-3) is well known to negatively regulate T-cell responses, but its role in CD8 T-cell exhaustion during chronic infection in vivo remains unclear. In this study, we document coregulation of CD8 T cell exhaustion by Tim-3 and PD-1 during chronic lymphocytic choriomeningitis virus infection. Whereas Tim-3 was only transiently expressed by CD8 T cells after acute infection, virus-specific CD8 T cells retained high Tim-3 expression throughout chronic infection. The majority (approximately 65% to 80%) of lymphocytic choriomeningitis virus-specific CD8 T cells in lymphoid and nonlymphoid organs coexpressed Tim-3 and PD-1. This coexpression of Tim-3 and PD-1 was associated with more severe CD8 T-cell exhaustion in terms of proliferation and secretion of effector cytokines such as IFN-gamma, TNF-alpha, and IL-2. Interestingly, CD8 T cells expressing both inhibitory receptors also produced the suppressive cytokine IL-10. Most importantly, combined blockade of Tim-3 and PD-1 pathways in vivo synergistically improved CD8 T cell responses and viral control in chronically infected mice. Taken together, our study defines a parameter for determining the severity of CD8 T cell dysfunction and for identifying virus-specific CD8 T cells that produce IL-10, and shows that targeting both PD-1 and Tim-3 is an effective immune strategy for treating chronic viral infections.

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    • "However, due to decreased splenic cellularity, the absolute numbers of T reg cells were actually reduced in chronically infected mice (Fig. 1 B). Punkosdy et al. (2011) (PD-1) and other inhibitory receptors such as Tim-3 and LAG-3 (Barber et al., 2006; Blackburn et al., 2009; Jin et al., 2010). Importantly , proliferation and function of exhausted T cells can be rescued by blockade of inhibitory pathways, which can result in restoration of effective immune responses that control infections and tumors (Barber et al., 2006; Fourcade et al., 2010; Sakuishi et al., 2010; Butler et al., 2012; Topalian et al., 2012). "
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