TGF-\(\beta\) and IL-10 Production by HIV-Specific CD8+ T Cells Is Regulated by CTLA-4 Signaling on CD4+ T Cells

Abstract

Immune dysregulation in HIV-1 infection is associated with increased expression of inhibitory molecules such as CTLA-4, TGF-\(\beta\), and IL-10. In this study we examined one potential mechanism for regulating TGF-\(\beta\) and IL-10 expression by HIV-specific suppressor CD8+ T cells. No overlap between TGF-\(\beta\), IL-10, and IFN-\(\gamma\) cytokine production by HIV-specific CD8+ T cells was observed. TGF-\(\beta\) positive and IL-10 positive cells were FOXP3 negative, CD25 negative, and displayed a heterogeneous surface expression of CD127. TGF-\(\beta\) 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-\(\beta\) positive and IL-10 positive CD8+ T cell responses, and a concomitant increase in HIV-specific IFN-\(\gamma\) positive CD8+ T cell responses. Depletion of CD4+ T cells abrogated the impact of CTLA-4 on HIV-specific TGF-\(\beta\) 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.