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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    • "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]. "
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    Cellular Immunology 12/2015; DOI:10.1016/j.cellimm.2015.10.009 · 1.92 Impact Factor
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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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    • "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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