RELA tunes innate-like interferon I/III responses in human T cells

In innate immune cells, intracellular sensors such as cGAS-STING stimulate type I/III interferon (IFN) expression, which promotes antiviral defense and immune activation. However, how IFN-I/III expression is controlled in adaptive cells is poorly understood. Here, we identify a transcriptional rheostat orchestrated by RELA that confers human T cells with innate-like abilities to produce IFN-I/III. Despite intact cGAS-STING signaling, IFN-I/III responses are stunted in CD4(+) T cells compared with dendritic cells or macrophages. We find that lysine residues in RELA tune the IFN-I/III response at baseline and in response to STING stimulation in CD4(+) T cells. This response requires positive feedback driven by cGAS and IRF7 expression. By combining RELA with IRF3 and DNA demethylation, IFN-I/III production in CD4(+) T cells reaches levels observed in dendritic cells. IFN-I/III production provides self-protection of CD4(+) T cells against HIV infection and enhances the elimination of tumor cells by CAR T cells. Therefore, innate-like functions can be tuned and leveraged in human T cells. A transcriptional rheostat orchestrated by RELA is found to control the expression of type I/III interferon in T cells. Unlocking IFN-I/III expression in T cells confers self-defense against HIV infection and increases the antitumor activity of CAR T cells.