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: 9.67). 08/2010; 107(33):14733-8. DOI: 10.1073/pnas.1009731107
Source: PubMed


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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    • "Amino acid substitution found in this receptor could affect their expression during disease progression. In gene expression studies, it was found that the expression of TIM- 3 in antiviral-specific CD4+ and CD8+ T cells contributes to immune exhaustion, which results in increased viral load and disease progression in chronic infection with LCMV (Jin et al., 2010) and HCV (Golden-Mason et al., 2009; McMahan et al., 2010). Detailed understanding of the negative signals this molecule transduce and of their interplay in T-lymphocytes may facilitate the genesis of more powerful and specific strategies for therapeutic manipulation of the immune system (Parry et al., 2005; Mingala et al., 2011). "
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    ABSTRACT: Molecular characterization of T-cell immunoglobulin mucin domain-3 (TIM-3) and Galectin-9 (GAL-9) genes of swamp- and riverine-type water buffaloes was conducted to compare these genes with other species; determine the unique characteristic specific in water buffalo; and provide baseline information for the assessment of disease progression in buffalo species. TIM-3 and GAL-9 genes were amplified, purified, sequenced and characterized. The sequence result of TIM-3 in both types of water buffaloes contained 843 nucleotides encoding to 280 amino acids while GAL-9 of swamp-type and riverine-type water buffaloes contained 1023 and 972 nucleotides encoding to 340 and 323 amino acids, respectively. Meanwhile, the nucleotide and amino sequence of TIM-3 in water buffalo were 83-98% and 94-97% identical with other artiodactyl species, respectively. On the other hand, GAL-9 nucleotide and amino acid sequence in water buffalo were 85-98% and 76-96% identical with other artiodactyl species. The tyrosine-kinase phosphorylation motif and potential glycosylation sites were conserved within the tribe Bovinae. It is imperative to have further studies in the assessment of the role of these genes in disease progression in water buffalo during chronic infection. The study is the first report that describes the genetic characteristic of TIM-3 and GAL-9 genes in water buffalo.
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    • "We found that, while most SMARTA cells showed substantial CD25 expression on day 1.5 p.i., TCF1 high T FH cells downregulated CD25 much faster than TCF1 low Th1 cells (Figure S1F). We also found that expression of Tim3, a co-inhibitory receptor expressed by exhausted CD8 T cells (Jin et al., 2010; Sakuishi et al., 2010), correlated well with Blimp1 (Figure S1F). We, therefore, used Tim3 as an early Th1 marker when the Blimp1-YFP reporter was not available. "
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    • "During chronic LCMV infections anti-viral T cells that co-express Tim-3 and PD-1 are less functional than their PD-1 þ Tim-3 À counterparts (Jin et al., 2010). Nevertheless, Tim-3 expression by M. tuberculosis-specific CD4 and CD8 T cells correlates with stronger IFN-γ and perforin production (Qiu et al., 2012). "
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    ABSTRACT: Although robust and highly effective anti-viral T cells contribute to the clearance of many acute infections, viral persistence is associated with the development of functionally inferior, exhausted, T cell responses. Exhaustion develops in a step-wise and progressive manner, ranges in severity, and can culminate in the deletion of the anti-viral T cells. This disarming of the response is consequential as it compromises viral control and potentially serves to dampen immune-mediated damage. Exhausted T cells are unable to elaborate typical anti-viral effector functions. They are characterized by the sustained upregulation of inhibitory receptors and display a gene expression profile that distinguishes them from prototypic effector and memory T cell populations. In this review we discuss the properties of exhausted T cells; the virological and immunological conditions that favor their development; the cellular and molecular signals that sustain the exhausted state; and strategies for preventing and reversing exhaustion to favor viral control. Copyright © 2014 Elsevier Inc. All rights reserved.
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