Histone deacetylases 1 and 2 restrain CD4+ cytotoxic T lymphocyte differentiation.

Some effector CD4(+) T cell subsets display cytotoxic activity, thus breaking the functional dichotomy of CD4(+) helper and CD8(+) cytotoxic T lymphocytes. However, molecular mechanisms regulating CD4(+) cytotoxic T lymphocyte (CD4(+) CTL) differentiation are poorly understood. Here we show that levels of histone deacetylases 1 and 2 (HDAC1-HDAC2) are key determinants of CD4(+) CTL differentiation. Deletions of both Hdac1 and 1 Hdac2 alleles (HDAC1(cKO)-HDAC2(HET)) in CD4(+) T cells induced a T helper cytotoxic program that was controlled by IFN-gamma-JAK1/2-STAT1 signaling. In vitro, activated HDAC1(cKO)-HDAC2(HET) CD4(+) T cells acquired cytolytic activity and displayed enrichment of gene signatures characteristic of effector CD8(+) T cells and human CD4(+) CTLs. In vivo, murine cytomegalovirus-infected HDAC1(cKO)-HDAC2(HET) mice displayed a stronger induction of CD4(+) CTL features compared with infected WT mice. Finally, murine and human CD4(+) T cells treated with short-chain fatty acids, which are commensal-produced metabolites acting as HDAC inhibitors, upregulated CTL genes. Our data demonstrate that HDAC1-HDAC2 restrain CD4(+) CTL differentiation. Thus, HDAC1-HDAC2 might be targets for the therapeutic induction of CD4(+) CTLs.