Article

PD-1 is a regulator of virus-specific CD8+ T cell survival in HIV infection

Immunology Laboratory, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Journal of Experimental Medicine (Impact Factor: 13.91). 11/2006; 203(10):2281-92. DOI: 10.1084/jem.20061496
Source: PubMed

ABSTRACT Here, we report on the expression of programmed death (PD)-1 on human virus-specific CD8(+) T cells and the effect of manipulating signaling through PD-1 on the survival, proliferation, and cytokine function of these cells. PD-1 expression was found to be low on naive CD8(+) T cells and increased on memory CD8(+) T cells according to antigen specificity. Memory CD8(+) T cells specific for poorly controlled chronic persistent virus (HIV) more frequently expressed PD-1 than memory CD8(+) T cells specific for well-controlled persistent virus (cytomegalovirus) or acute (vaccinia) viruses. PD-1 expression was independent of maturational markers on memory CD8(+) T cells and was not directly associated with an inability to produce cytokines. Importantly, the level of PD-1 surface expression was the primary determinant of apoptosis sensitivity of virus-specific CD8(+) T cells. Manipulation of PD-1 led to changes in the ability of the cells to survive and expand, which, over several days, affected the number of cells expressing cytokines. Therefore, PD-1 is a major regulator of apoptosis that can impact the frequency of antiviral T cells in chronic infections such as HIV, and could be manipulated to improve HIV-specific CD8(+) T cell numbers, but possibly not all functions in vivo.

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    ABSTRACT: Chronic HIV infection results in a loss of HIV-specific CD8+ T cell effector function, termed "exhaustion", which is mediated, in part, by the membrane co-inhibitory receptor T cell immunoglobulin mucin domain-3 (Tim-3). Like many other receptors, a soluble form of this protein has been described in human blood plasma. However, soluble Tim-3 (sTim-3) is poorly characterized and its role in HIV disease is unknown. Here we show that Tim-3 is shed from the surface of responding CD8+ T cells by the matrix metalloproteinase, ADAM10, producing a soluble form of the co-inhibitory receptor. Despite previous reports in the mouse model, no alternatively spliced, soluble form of Tim-3 was observed in humans. Shed sTim-3 was found in human plasma, and was significantly elevated during early and chronic untreated HIV infection, but was not found differentially modulated in HAART treated HIV-infected subjects or in elite controllers, when compared to HIV-uninfected subjects. Plasma sTim-3 levels positively correlated with HIV viral load and negatively correlated with CD4 counts. Thus, plasma sTim-3 shedding correlated with HIV disease progression. Despite these correlations, we found that shedding Tim-3 did not improve the function of CD8+ T cells in terms of IFN-γ production or prevent their apoptosis through galectin-9. Further characterization studies of sTim-3 function are needed to understand the contribution of sTim-3 in HIV disease pathogenesis with implications for novel therapeutic interventions. (224/250) IMPORTANCE: Despite the overall success of HAART slowing the progression to AIDS in HIV-infected subjects, chronic immune activation and T cell exhaustion contribute to the eventual deterioration of the immune system. Understanding these processes will aid in the development of interventions and therapeutics to be used in combination with HAART to slow or reverse this deterioration. Here, we show that a soluble form of T cell exhaustion associated co-inhibitory molecule, Tim-3, is shed from the surface of T cells. Furthermore, sTim-3 is elevated in the plasma of treatment naïve subjects with acute and chronic HIV infection and is associated with markers of disease progression. This is the first study to characterize sTim-3 in human plasma, its source and mechanism of production. While it is still unclear whether sTim-3 contributes to HIV pathogenesis, sTim-3 may represent a new correlate of HIV disease progression. (141/150). Copyright © 2015, American Society for Microbiology. All Rights Reserved.
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    ABSTRACT: Virus-specific CD8+ T cells play an important role in controlling viral infections including human immunodeficiency virus (HIV) infection. However, during chronic HIV infection, virus-specific CD8+ T cells undergo functional exhaustion, lose effector functions and fail to control viral infection. HIV-specific CD8 T cells expressing high levels of co-inhibitory molecule programmed death-1 (PD-1) during the chronic infection and are characterized by lower proliferation, cytokine production, and cytotoxic abilities. Although, antiretroviral therapy has resulted in dramatic decline in HIV replication, there is no effective treatment currently available to eradicate viral reservoirs or restore virus-specific T or B-cell functions that may complement ART in order to eliminate the virus. In recent years, studies in mice and non-human primate models of HIV infection demonstrated the functional exhaustion of virus-specific T and B cells could be reversed by blockade of interaction between PD-1 and its cognate ligands (PD-L1 and PD-L2). In this review, we discuss recent advances in our understanding of PD-1 pathway in HIV/SIV infection and discuss the beneficial effects of PD-1 blockade during chronic HIV/SIV infection and its potential role as immunotherapy for HIV/AIDS.
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    ABSTRACT: The inhibitory receptor T-cell immunoglobulin and mucin domain-3 (Tim-3) has emerged as a critical regulator of the T-cell dysfunction that develops in chronic viral infections and cancers. However, little is known regarding the signalling pathways that drive Tim-3 expression. Here, we demonstrate that interleukin (IL)-27 induces nuclear factor, interleukin 3 regulated (NFIL3), which promotes permissive chromatin remodelling of the Tim-3 locus and induces Tim-3 expression together with the immunosuppressive cytokine IL-10. We further show that the IL-27/NFIL3 signalling axis is crucial for the induction of Tim-3 in vivo. IL-27-conditioned T helper 1 cells exhibit reduced effector function and are poor mediators of intestinal inflammation. This inhibitory effect is NFIL3 dependent. In contrast, tumour-infiltrating lymphocytes from IL-27R(-/-) mice exhibit reduced NFIL3, less Tim-3 expression and failure to develop dysfunctional phenotype, resulting in better tumour growth control. Thus, our data identify an IL-27/NFIL3 signalling axis as a key regulator of effector T-cell responses via induction of Tim-3, IL-10 and T-cell dysfunction.
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