HIV-Specific TGF- β -Positive CD4 + T Cells Do Not Express Regulatory Surface Markers and Are Regulated by CTLA-4

Abstract

CD4⁺ T cell dysfunction in HIV-1 infection is associated with increased CTLA-4 and TGF-β expression. In this study we described a population of TGF-β-positive CD4⁺ T cells with multiple HIV specificities. These HIV-specific TGF-β-positive CD4⁺ T cells did not display the immunophenotypic patterns traditionally attributed to regulatory CD4⁺ T cells. TGF-β-positive CD4⁺ T cells were FOXP3 negative, CD25 negative, and displayed a heterogeneous surface expression of CD127. We also examined one potential mechanism for regulating TGF-β expression by HIV-specific CD4⁺ T cells. Blocking of the TGF-β receptor II led to increased HIV-specific IFN-γ-positive CD4⁺ and CD8⁺ T cell responses. Interestingly, HIV-specific TGF-β-positive CD4⁺ T cells did not substantially express CTLA-4. Nevertheless, CTLA-4 blockade resulted in a significant decrease in HIV-specific TGF-β-positive CD4⁺ T cell responses, and a concomitant increase in HIV-specific IFN-γ-positive CD4⁺ T cell responses. Our study proposes a mechanism by which HIV-specific TGF-β production may be regulated by CTLA-4 engagement.