Abstract
Expression of co-inhibitory molecules is generally associated with T-cell dysfunction in chronic viral infections such as HIV or HCV. However, their relative contribution in the T-cell impairment remains unclear. In the present study, we have evaluated the impact of the expression of co-inhibitory molecules such as 2B4, PD-1 and CD160 on the functions of CD8 T-cells specific to influenza, EBV and CMV. We show that CD8 T-cell populations expressing CD160, but not PD-1, had reduced proliferation capacity and perforin expression, thus indicating that the functional impairment in CD160+ CD8 T cells may be independent of PD-1 expression. The blockade of CD160/CD160-ligand interaction restored CD8 T-cell proliferation capacity, and the extent of restoration directly correlated with the ex vivo proportion of CD160+ CD8 T cells suggesting that CD160 negatively regulates TCR-mediated signaling. Furthermore, CD160 expression was not up-regulated upon T-cell activation or proliferation as compared to PD-1. Taken together, these results provide evidence that CD160-associated CD8 T-cell functional impairment is independent of PD-1 expression.
Highlights
Co-stimulatory and co-inhibitory molecules play a major role in the regulation of antigen-specific T-cell responses [1]
We demonstrated that CD160+ CD8 T cells had reduced proliferation capacity, IL-2 production and perforin expression regardless of PD-1 expression providing evidence that CD160-associated T-cell impairment is independent of PD-1
We demonstrate that CD160-associated CD8 T-cell functional impairment is independent of PD-1 expression and that the blockade of CD160 signaling may partially restore CD8 T-cell functions
Summary
Co-stimulatory and co-inhibitory molecules play a major role in the regulation of antigen-specific T-cell responses [1]. Many studies performed in mice and humans have underscored the role of co-inhibitory molecules in the functional impairment ( called ‘‘exhaustion’’) of antigenspecific T cells during chronic viral infections such as human immunodeficiency virus-1 (HIV-1) or hepatitis C virus (HCV) [11,12,13,14]. In these virus chronic infections, the early functional impairment of T cells was marked by the loss of proliferation capacity likely resulting from reduced capacity to produce IL-2 and a deficient killing capacity of CD8 T cells. The ability to produce TNF-a was generally observed at an intermediate state of T-cell exhaustion while the loss of IFN-c occurred in the advanced stage of T-cell exhaustion [15,16]
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