A type-1 immunity-restricted promoter of the IL-33 receptor gene directs antiviral T cell responses

Abstract The pleiotropic alarmin interleukin-33 (IL-33) drives type-1, type-2, and regulatory T-cell responses via its receptor ST2. Subset-specific differences in ST2 expression intensity and dynamics suggest that transcriptional regulation is key in orchestrating the context-dependent activity of IL-33-ST2 signaling in T-cell immunity. Here, we identify a previously unrecognized alternative promoter in mice and humans that is located far upstream of the curated ST2-coding gene and drives ST2 expression in type-1 immunity. Mice lacking this promoter exhibit a selective loss of ST2 expression in type-1- but not type-2-biased immune cells, resulting in impaired expansion of cytotoxic T cells (CTLs) and T-helper-1 cells upon viral infection. T-cell-intrinsic IL-33 signaling via type-1 promoter-driven ST2 is critical to generate a clonally diverse population of antiviral short-lived effector CTLs. Thus, lineage-specific alternative promoter usage directs alarmin responsiveness in T-cell subsets and offers opportunities for immune cell-specific targeting of the IL-33-ST2 axis in infections and inflammatory diseases.