Ryanodine Receptor 1 Is Dispensable for CD4⁺ T-Cell Differentiation and Effector Function in Intestinal Inflammation...

T-cell receptor (TCR) 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 TCR 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 supported 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 Ca²⁺ microdomain formation, reduced peak Ca²⁺ amplitude, and delayed the 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.