Calcium signals in lymphocyte activation and disease

Abstract

Calcium ions function as universal second messengers in virtually all eukaryotic cells including cells of the immune system where they are crucial for the function of T and B cells, mast cells and dendritic cells. The predominant mechanism regulating intracellular Ca2+ levels in cells of the adaptive immune system is store-operated Ca2+ influx through so-called Ca2+−release activated Ca2+ (CRAC) channels. We identified ORAI1 (also named CRACM1) as a pore subunit of the CRAC channel essential for the function of T cells and mast cells. Mutation of ORAI1 in humans is associated with severe combined immunodeficiency (SCID), increased susceptibility to infections and a failure to thrive. ORAI1/CRAC channels are activated when intracellular Ca2+ stores are depleted. The resulting decrease in the ER Ca2+ concentration is sensed by stromal interaction molecule 1 (STIM1) that is required for activation of ORAI1/CRAC channels. We showed that murine T cells lacking STIM1 exhibit severely impaired store-operated Ca2+ influx. T cells from mice lacking STIM1 or its paralogue STIM2 both showed significantly reduced cytokine production in vitro and a defect in regulatory T cell development as well as lympho- and myeloproliferation in vivo. T cells from mice transgenic for an R91W mutation in ORAI1 that abrogates CRAC channel function in T cells from human SCID patients also showed substantially impaired store-operated Ca2+ influx and cytokine gene expression. This important role of STIM1 and ORAI1 in T cell function in mice is also apparent in T cells from human patients with SCID, which lack expression of ORAI1 and STIM1, respectively. Taken together STIM1, STIM2 and ORAI1 are essential regulators of store-operated Ca2+ entry in cells of the immune system and other tissues.