We identified the first patients with loss-of-function mutations in ORAI1 or STIM1, describing a new syndrome — CRAC channelopathy — characterized by combined immunodeficiency with recurrent infections, autoimmunity, muscular hypotonia, and ectodermal dysplasia. The severe susceptibility to infection in these patients underscores the non-redundant role of CRAC channel-mediated calcium signaling in adaptive immunity and provides a compelling human model for understanding how SOCE shapes immune defense. Using mice with genetic deletion of ORAI and STIM homologues, we demonstrated that CRAC channels are essential for cytotoxic CD8⁺ T cell responses to viral infection, CD4⁺ Th1 and T follicular helper (Tfh) cell responses to viral infection, and CD4⁺ T cell immunity to fungal and chronic mycobacterial infections — collectively providing a mechanistic basis for the immunodeficiency observed in CRAC channelopathy. Notably, the same pathway drives CD8⁺ T cell-mediated antitumor immunity across multiple cancer models.
CRAC channels also play essential roles in immune tolerance by controlling the differentiation and function of proinflammatory CD4⁺ T cell subsets. In animal models of inflammatory bowel disease, psoriasis, and multiple sclerosis, genetic deletion or pharmacological inhibition of CRAC channels attenuates Th1 and Th17 responses and reduces disease activity. CRAC channels similarly drive allergic asthma by regulating cell cycle progression and Th2 cell-defining transcription factors and cytokines. These pathogenic roles of are counterbalanced by CRAC channel function in regulatory T (Treg) cells, where calcium signals are required for thymic Treg development and the differentiation of tissue-resident Tregs and T follicular regulatory cells. Mice lacking CRAC channels in Tregs develop multiorgan autoimmunity resembling Sjögren’s disease, driven by elevated IFN-γ production. Together, our findings define a therapeutic window in which partial CRAC channel inhibition suppresses pathogenic inflammation while preserving immune tolerance and host defense.
Ongoing work in the lab continues to explore the roles of CRAC channels in infection, asthma, and autoimmune diseases including Sjögren’s disease and lupus.