Our laboratory has made seminal contributions to understanding the CRAC channel, beginning with the landmark discovery of ORAI1 as its pore-forming subunit. Leveraging genetically engineered mouse models with targeted deletion of ORAI1 and its homologues ORAI2 and ORAI3, as well as their activators STIM1 and STIM2, we have systematically dissected how CRAC channel-mediated calcium signaling governs immune cell physiology. Our studies revealed that CRAC channels control the expression of hundreds of genes in T cells, including cytokines and lineage-defining transcription factors that direct the differentiation of CD4⁺ T cells into distinct effector subsets, including Th1, Th2, Th17, and regulatory T (Treg) cells. In addition, CRAC channels drive key metabolic programs — encompassing glycolysis, mitochondrial respiration, and lipid metabolism — that are required to sustain T cell proliferation and proinflammatory effector functions. Collectively, these studies established ORAI and STIM proteins as the core molecular components of the CRAC channel and defined their essential roles in adaptive immunity.
Building on this foundation, we are investigating the molecular and immunological mechanism how CRAC channel-mediated calcium signals promote the differentiation of CD4⁺ T cells into T follicular helper (Tfh) cells, which are critical orchestrators of humoral immune responses in the context of infection and autoimmunity. In parallel, we are exploring how intracellular calcium homeostasis, governed by organellar calcium handling proteins, regulates B cell development into antibody-secreting plasma cells. Together, these studies provide fundamental insights into calcium signaling in lymphocyte biology and identify novel therapeutic targets for modulating humoral immunity in disease.