Ryanodine Receptor 1 Is Dispensable for CD4 + T‐Cell Differentiation and Effector Function in Intestinal Inflammation Models
Sogol Dostiar Tabrizi, Mikolaj Nawrocki, Tanja Bedke, Marius Böttcher, Friederike Stumme, Melina Birus, Franziska Möckl, Lola Hernandez, Björn‐Phillip Diercks, Nicola Gagliani, Dmitri Lodygin, Alexander Flügel, Andreas H. Guse, Hans‐Willi Mittrücker, Samuel HuberABSTRACT
T‐cell receptor (TCR) 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 TCR 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 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 Ca 2+ microdomain formation, reduced peak Ca 2+ amplitude, and delayed the 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.