Surface expression patterns of negative regulator molecules identify determinants of virus specific CD8 T cell exhaustion in HIV infection

National Institutes of Health, Bethesda, MD, USA.
Blood (Impact Factor: 10.45). 03/2011; 117(18):4805-15. DOI: 10.1182/blood-2010-11-317297
Source: PubMed


A highly complex network of coinhibitory and costimulatory receptors regulates the outcome of virus-specific CD8(+) T-cell responses. Here, we report on the expression patterns of multiple inhibitory receptors on HIV-specific, cytomegalovirus-specific, and bulk CD8(+) T-cell memory populations. In contrast to cytomegalovirus-specific CD8(+) T cells, the majority of HIV-specific CD8(+) T cells exhibited an immature phenotype and expressed Programmed Death-1, CD160 and 2B4 but not lymphocyte activation gene-3. Notably, before antiretroviral therapy, simultaneous expression of these negative regulators correlated strongly with both HIV load and impaired cytokine production. Suppression of HIV replication by antiretroviral therapy was associated with reduced surface expression of inhibitory molecules on HIV-specific CD8(+) T cells. Furthermore, in vitro manipulation of Programmed Death-1 and 2B4 inhibitory pathways increased the proliferative capacity of HIV-specific CD8(+) T cells. Thus, multiple coinhibitory receptors can affect the development of HIV-specific CD8(+) T-cell responses and, by extension, represent potential targets for new immune-based interventions in HIV-infected persons.

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Available from: Peter D Katsikis, Sep 08, 2014
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    • "CTL function directly correlates with the number of inhibitory receptors expressed [20] [21]. Based on our findings, CD160+CD8+ T cells were preferentially positive for 2B4 relative to PD1. "
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    ABSTRACT: HTLV-1 infection is a life-long retroviral infection. Chronic viral antigenic stimulation induces persistent infection which results in a clinically asymptomatic carrier state. Only a minor proportion of infected individuals develop adult T cell leukemia/lymphoma (ATLL) or HTLV-1-associated myelopathy/tropical spastic myelopathy (HAM/TSP). This is dependent on a balance of host and genetic factors. CD8+ cytotoxic T lymphocyte function is important in the immune response against viral infection; however, the contribution of CD160 receptor associated with CD8+ T lymphocytes is unclear. Thus, we sought to decipher its role on CTL function in HTLV-1 infection. Here, we report high frequencies of CD160 on CD8+ T cells, with significantly higher levels on HTLV-1 specific CD8+ T cells. Intercepting the CD160 pathway via blockade of the receptor or its ligand, herpes virus entry mediator (HVEM) resulted in improved perforin production and CD107a degranulation of HTLV-1 specific CD8+ T cells. Analysis of the CD160-expressing CD8+ cells demonstrated a unique subset associated with a highly differentiated effector memory based on CD45RA and CCR7 co-expression, increased expression of inhibitory molecules, 2B4 and PD1. Altogether, these results suggest a role for CD160/HVEM pathway in regulating immune response against HTLV-1 infection which may prove promising in the development of immune therapies for the treatment of HTLV-1 infection and other associated disorders.
    Biochemical and Biophysical Research Communications 09/2014; 453(3). DOI:10.1016/j.bbrc.2014.09.084 · 2.30 Impact Factor
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    • "It was suggested that reversing T cell exhaustion could restore effective immune response, and subsequently control tumor progress and virus amplification.6-10 Exhausted T cells are characterized by expressing multiple inhibitory receptors which dedicated complex layers of negative regulation.11-13 Programmed death-1 (PD-1), T lymphocyte antigen 4 (CTLA-4), and B and T lymphocyte attenuator (BTLA), currently constituting the immunoglobulin superfamily of coinhibitory molecules, play a prominent role in effectively and moderately regulating immune response in collaboration with costimulatory molecules as well as T cell receptor-antigen signals.14-18 "
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    ABSTRACT: Programmed death-1 (PD-1) expression was investigated in CD4(+) and CD8(+) T cells from hepatitis B virus (HBV)-infected patients at the chronic hepatitis B (CHB) infection, liver cirrhosis (LC), and hepatocellular carcinoma (HCC) stages. PD-1 expression in circulating CD4(+) and CD8(+) T cells was detected by flow cytometry. The correlations between PD-1 expression and HBV viral load, alanine aminotransaminase (ALT) levels and aspartate aminotransferase (AST) levels were analyzed using GraphPad Prism 5.0. PD-1 expression in CD4(+) and CD8(+) T cells was significantly increased in both the CHB group and advanced-stage group (LC plus HCC). In the CHB group, PD-1 expression in both CD4(+) and CD8(+) T cells was positively correlated with the HBV viral load, ALT, and AST levels. However, in the LC plus HCC group, significant correlations between PD-1 expression and the clinical parameters were nearly absent. PD-1 expression in peripheral CD4(+) and CD8(+) T cells is dynamic, changes with HBV infection progression, and is related to HBV viral load and liver function, especially in CHB. PD-1 expression could be utilized as a potential clinical indicator to determine the extent of virus replication and liver injury.
    Gut and Liver 03/2014; 8(2):186-95. DOI:10.5009/gnl.2014.8.2.186 · 1.81 Impact Factor
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    • "Further, the proportion of 2B4+CD8+ T cells is associated with immune activation of memory T cells, which increases with disease progression [80]. It is also clear that the ability to produce IFN-γ and cytotoxic activity of HIV-specific 2B4+CD8+ T cells is relatively lower compared to influenza-specific 2B4+CD8+ T cells in HIV infected individuals [81], and in vitro blockade of 2B4 increases the proliferative capacity of HIV-specific CD8+ T cells [82]. Moreover, downregulation of SAP in 2B4+CD8+ T cells upon HIV stimulation suggests an inhibitory role of 2B4+CD8+ T cells against constrained HIV epitopes, underlining the inability to control HIV during disease progression. "
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    ABSTRACT: Cellular immune responses play a crucial role in the control of viral replication in HIV-infected individuals. However, the virus succeeds in exploiting the immune system to its advantage and therefore, the host ultimately fails to control the virus leading to development of terminal AIDS. The virus adopts numerous evasion mechanisms to hijack the host immune system. We and others recently described the expression of inhibitory molecules on T cells as a contributing factor for suboptimal T-cell responses in HIV infection both in vitro and in vivo. The expression of these molecules that negatively impacts the normal functions of the host immune armory and the underlying signaling pathways associated with their enhanced expression need to be discussed. Targets to restrain the expression of these molecular markers of immune inhibition is likely to contribute to development of therapeutic interventions that augment the functionality of host immune cells leading to improved immune control of HIV infection. In this review, we focus on the functions of inhibitory molecules that are expressed or secreted following HIV infection such as BTLA, CTLA-4, CD160, IDO, KLRG1, LAG-3, LILRB1, PD-1, TRAIL, TIM-3, and regulatory cytokines, and highlight their significance in immune inhibition. We also highlight the ensemble of transcriptional factors such as BATF, BLIMP-1/PRDM1, FoxP3, DTX1 and molecular pathways that facilitate the recruitment and differentiation of suppressor T cells in response to HIV infection.
    Retrovirology 03/2013; 10(1):31. DOI:10.1186/1742-4690-10-31 · 4.19 Impact Factor
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