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bioRxiv · 10.64898/2026.01.14.699480

Ryanodine receptor 1 is dispensable for CD4+ T-cell differentiation and effector function in intestinal inflammation models

Tabrizi, S. D.·Nawrocki, M.·Diercks, B.-P.·Bedke, T.·Boettcher, M.·Stumme, F.·Birus, M.·Moeckl, F.·Hernandez, L.·Gagliani, N.·Lodygin, D.·Fluegel, A.·Guse, A. H.·Mittruecker, H.-W.·Huber, S.
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Abstract

T-cell receptor signaling is necessary for the activation and differentiation of CD4 T cells. Calcium (Ca2+) signaling is essential for this process, and the complexity of Ca2+ channels presents a potential therapeutic target for modulating the strength of T-cell receptor signaling and further differentiation of CD4 T cells. Nicotinic acid adenine dinucleotide phosphate (NAADP) is a potent Ca2+-mobilizing second messenger that triggers Ca2+ release through ryanodine receptor 1 (RYR1) in T cells. While the molecular and biophysical properties of NAADP-induced Ca2+ microdomains in T cells have been thoroughly investigated, and the function of the NAADP-HN1L/JPT2-RYR1 axis has been proven in T-cell activation and proliferation, its role in intestinal inflammation in vivo remains to be elucidated. In this study, we generated a conditional knockout mouse with Ryr1 deleted in {beta} T cells to investigate the functional relevance of RYR1 signaling in CD4 T cells. Ryr1 deletion in CD4+ T cells decreased TCR-induced Ca2+ microdomain formation, reduced peak Ca2+ amplitude and delayed initial velocity of global Ca2+ signaling in vitro. However, Ryr1 expression in CD4 T cells was dispensable for their pathogenicity in murine models of intestinal inflammation. Thus, Ryr1 expression in CD4+ T cells plays a redundant role in intestinal inflammation.

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Tabrizi, S. D., Nawrocki, M., Diercks, B.-P., Bedke, T., Boettcher, M., Stumme, F., Birus, M., Moeckl, F., Hernandez, L., Gagliani, N., Lodygin, D., Fluegel, A., Guse, A. H., Mittruecker, H.-W., Huber, S.. 2026-01-15. Ryanodine receptor 1 is dispensable for CD4+ T-cell differentiation and effector function in intestinal inflammation models. https://doi.org/10.64898/2026.01.14.699480

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