Differential CTLA-4 expression in human CD4 + versus CD8 + T cells is associated with increased NFAT1 and inhibition of CD4 + proliferation

Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) is a costimulatory molecule that negatively regulates T-cell activation. Originally identified in murine CD8 + T cells, it has been found to be rapidly induced on human T cells. Furthermore, CTLA-4 is expressed on regulatory T cells. Clinically, targeting CTLA-4 has clinical utility in the treatment of melanoma. Whether the expression of CTLA-4 is differentially regulated in CD8 + vs CD4 + human T cells is unclear. Here, we analyzed CTLA-4 in normal human CD4 + and CD8 + T-cell subsets and show for the first time that CTLA-4 is expressed significantly higher in the CD4 + T cells than in CD8 + T cells. CTLA-4 is higher at the protein and the transcriptional levels in CD4 + T cells. This increase is due to the activation of the CTLA-4 promoter, which undergoes acetylation at the proximal promoter. Furthermore, we show that blocking CTLA-4 on CD4 + T cells permits greater proliferation in CD4 + vs CD8 + cells. These findings demonstrate a differential regulation of CTLA-4 on CD4 + and CD8 + T-cell subsets, which is likely important to the clinical efficacy for anti-CTLA-4 therapies. The findings hint to strategies to modulate CTLA-4 expression by targeting epigenetic transcription to alter the immune response.