Abstract
Immune dysregulation in HIV-1 infection is associated with increased expression of inhibitory molecules such as CTLA-4, TGF-β, and IL-10. In this study we examined one potential mechanism for regulating TGF-β and IL-10 expression by HIV-specific suppressor CD8+ T cells. No overlap between TGF-β, IL-10, and IFN-γ cytokine production by HIV-specific CD8+ T cells was observed. TGF-β positive and IL-10 positive cells were FOXP3 negative, CD25 negative, and displayed a heterogeneous surface expression of CD127. TGF-β and IL-10 positive CD8+ T cells did not express CTLA-4. Nevertheless, CTLA-4 blockade resulted in a significant decrease in HIV-specific TGF-β positive and IL-10 positive CD8+ T cell responses, and a concomitant increase in HIV-specific IFN-γ positive CD8+ T cell responses. Depletion of CD4+ T cells abrogated the impact of CTLA-4 on HIV-specific TGF-β positive and IL-10 positive CD8+ T cells. Our study suggests that CTLA-4 Signaling on CD4+ T cells regulates the inhibitory functions of the HIV-specific suppressor CD8+ T cells.
Highlights
Suppressor CD8+ T cells (CD8+ Ts) exert their inhibitory effects on T cell proliferation and cytokine production through a cell-cell contact-dependent mechanism [1,2,3,4], and by secreting the immunosuppressive cytokines interleukin-10 and Transforming growth factor b (TGF-b) [5,6]
We explore the relationship between Cytotoxic T lymphocyte antigen 4 (CTLA-4) positive CD4+ T cells and the production of TGF-b and IL-10 by HIV-specific CD8+ T cells
We first measured the frequency of Gag and Nef-specific TGF-b positive and IL-10 positive CD8+ T cells in 37 HIV-1 infected volunteers (Fig. 1A)
Summary
Suppressor CD8+ T cells (CD8+ Ts) exert their inhibitory effects on T cell proliferation and cytokine production through a cell-cell contact-dependent mechanism [1,2,3,4], and by secreting the immunosuppressive cytokines interleukin-10 and TGF-b [5,6]. CD8+ Ts mediate non-antigen specific suppression of T cell responses via IL-10 [7,8,9,10] These suppressor CD8+ T cells are typically CD28 negative [11,12] and express CD25, FOXP3, and CTLA-4 [1,4,13,14]. TGF-b up-regulates CTLA-4 expression [19,20,21] and suppresses T cell proliferation and IL-2 production [22]. Increased TGF-b and IL-10 is associated with disease progression in HIV-1infected patients [23,24], and likely influences the antiviral immune responses [23,24,25]
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