ABSTRACT
CD4(+) T cell dysfunction in HIV-1 infection is associated with increased CTLA-4 and TGF-beta expression. In this study we described a population of TGF-beta-positive CD4(+) T cells with multiple HIV specificities. These HIV-specific TGF-beta-positive CD4(+) T cells did not display the immunophenotypic patterns traditionally attributed to regulatory CD4(+) T cells. TGF-beta-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-beta expression by HIV-specific CD4(+) T cells. Blocking of the TGF-beta receptor II led to increased HIV-specific IFN-gamma-positive CD4(+) and CD8(+) T cell responses. Interestingly, HIV-specific TGF-beta-positive CD4(+) T cells did not substantially express CTLA-4. Nevertheless, CTLA-4 blockade resulted in a significant decrease in HIV-specific TGF-beta-positive CD4(+) T cell responses, and a concomitant increase in HIV-specific IFN-gamma-positive CD4(+) T cell responses. Our study proposes a mechanism by which HIV-specific TGF-beta production may be regulated by CTLA-4 engagement.
Subject(s)
Antigens, CD/metabolism , CD4-Positive T-Lymphocytes/metabolism , Forkhead Transcription Factors/biosynthesis , HIV Infections/immunology , HIV-1 , Interleukin-2 Receptor alpha Subunit/biosynthesis , Interleukin-7 Receptor alpha Subunit/biosynthesis , Adaptive Immunity , Antigens, CD/immunology , Antigens, Surface/biosynthesis , Antigens, Surface/immunology , CD4-Positive T-Lymphocytes/immunology , CTLA-4 Antigen , Forkhead Transcription Factors/immunology , HIV Infections/metabolism , HIV Infections/virology , Humans , Interferon-gamma/biosynthesis , Interferon-gamma/immunology , Interleukin-2 Receptor alpha Subunit/immunology , Interleukin-7 Receptor alpha Subunit/immunology , Protein Serine-Threonine Kinases/immunology , Protein Serine-Threonine Kinases/metabolism , Receptor, Transforming Growth Factor-beta Type II , Receptors, Transforming Growth Factor beta/immunology , Receptors, Transforming Growth Factor beta/metabolism , Transforming Growth Factor beta/biosynthesis , Transforming Growth Factor beta/immunologyABSTRACT
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.
