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.

Download full-text


Available from: Peter D Katsikis, Sep 08, 2014
  • Source
    • "Most HIV-specific CD8+ T cells are highly skewed towards a Tbet dim Eomes hi profile, while CMV-specific CD8+ T cells from the same donors showed a more balanced expression pattern between the two transcription factors. Importantly, the differential expression pattern between T-bet and Eomes was not reversed despite long-term antiretroviral therapy (ART), and was highly associated with an exhausted phenotype (increased PD-1, CD160, 2B4 expression and poor effector differentiation), thereby recapitulating the findings from previous studies conducted in mice [60] [61]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Understanding the mechanisms involved in cellular immune responses against control of human immunodeficiency virus (HIV) infection is key to development of effective immunotherapeutic strategies against viral proliferation. Clear insights into the regulation of cytotoxic CD8+ T cells is crucial to development of effective immunotherapeutic strategies due to their unique ability to eliminate virus-infected cells during the course of infection. Here, we reviewed the roles of transcription factors, co-inhibitory molecules and regulatory cytokines following HIV infection and their potential significance in regulating the cytotoxic potentials of CD8+ T cells.
    Full-text · Article · Dec 2015 · Cellular Immunology
  • Source
    • "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. "
    [Show abstract] [Hide abstract]
    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.
    Full-text · Article · Sep 2014 · Biochemical and Biophysical Research Communications
  • Source
    • "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 "
    [Show abstract] [Hide abstract]
    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.
    Full-text · Article · Mar 2014 · Gut and Liver
Show more