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