Store-Operated Calcium Entry (SOCE) Controls Innate and Adaptive Immune Cell Function in IBD

IBD is characterized by dysregulated intestinal immune responses. Using mass cytometry to analyze immune cells from the lamina propria (LP) of patients with ulcerative colitis and Crohn's disease, we here observed that the LP of IBD patients is enriched with CD4+ T cell cells producing IL-17A and TNF, regulatory T cells, CD8+ T cells and innate lymphoid cells (ILCs). The function of these immune cells is regulated by store-operated Ca2+ entry (SOCE) mediated by ORAI and STIM proteins. We observed that the pharmacologic inhibition of SOCE attenuated the production of pathogenic cytokines including IL-2, IL-4, IL-6, IL-17A, TNF, and IFNγ by human colonic T cells and ILCs, reduced the production of IL-6 by B cells and the production of IFNγ by myeloid cells, without affecting the viability, differentiation, and function of primary intestinal epithelial cells. Genetic deletion of SOCE-signaling-components revealed that the magnitude of SOCE correlates with the function of T cells and intestinal inflammation in mice. Moreover, pharmacologic SOCE-inhibition alleviated colitis in mice, suggesting that SOCE-inhibition may serve as a new drug-target in IBD.