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

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Item Type:Article
Title:A type 1 immunity-restricted promoter of the IL-33 receptor gene directs antiviral T-cell responses
Creators Name:Brunner, T.M. and Serve, S. and Marx, A.F. and Fadejeva, J. and Saikali, P. and Dzamukova, M. and Durán-Hernández, N. and Kommer, C. and Heinrich, F. and Durek, P. and Heinz, G.A. and Höfer, T. and Mashreghi, M.F. and Kühn, R. and Pinschewer, D.D. and Löhning, M.
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 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.
Keywords:Alarmins, Antiviral Agents, Interleukin-1 Receptor-Like 1 Protein, Interleukin-33, T-Lymphocyte Subsets / Metabolism, Animals, Mice
Source:Nature Immunology
Publisher:Nature Publishing Group
Page Range:256-267
Date:February 2024
Official Publication:https://doi.org/10.1038/s41590-023-01697-6
PubMed:View item in PubMed

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