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


  • T.M. Brunner
  • S. Serve
  • A.F. Marx
  • J. Fadejeva
  • P. Saikali
  • M. Dzamukova
  • N. Durán-Hernández
  • C. Kommer
  • F. Heinrich
  • P. Durek
  • G.A. Heinz
  • T. Höfer
  • M.F. Mashreghi
  • R. Kühn
  • D.D. Pinschewer
  • M. Löhning


  • Nature Immunology


  • Nat Immunol 25 (2): 256-267


  • 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 T 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.