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

Abstract T-cell receptor signaling is necessary for the activation and differentiation of CD4⁺ T cells. Calcium (Ca 2+ ) signaling is essential for this process, and the complexity of Ca 2+ 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 Ca 2+ -mobilizing second messenger that triggers Ca 2+ release through ryanodine receptor 1 (RYR1) in T cells. While the molecular and biophysical properties of NAADP-induced Ca 2+ 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 αβ T cells to investigate the functional relevance of RYR1 signaling in CD4⁺ T cells. Ryr1 deletion in CD4 + T cells decreased TCR-induced Ca 2+ microdomain formation, reduced peak Ca 2+ amplitude and delayed initial velocity of global Ca 2+ 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.