Dual functions for the endoplasmic reticulum calcium sensors STIM1 and STIM2 in T cell activation and tolerance

Abstract

Store-operated Ca2+ entry through calcium release-activated calcium channels is the chief mechanism for increasing intracellular Ca2+ in immune cells. Here we show that mouse T cells and fibroblasts lacking the calcium sensor STIM1 had severely impaired store-operated Ca2+ influx, whereas deficiency in the calcium sensor STIM2 had a smaller effect. However, T cells lacking either STIM1 or STIM2 had much less cytokine production and nuclear translocation of the transcription factor NFAT. T cell-specific ablation of both STIM1 and STIM2 resulted in a notable lymphoproliferative phenotype and a selective decrease in regulatory T cell numbers. We conclude that both STIM1 and STIM2 promote store-operated Ca2+ entry into T cells and fibroblasts and that STIM proteins are required for the development and function of regulatory T cells.

STIM1 and STIM2 protein deficiency in T lymphocytes underlies development of the exocrine gland autoimmune disease, Sjögren's syndrome

“…Studies in mice have also led to similar conclusions. Whereas global deletion of Orai1, STIM1, or STIM2 in mice results in premature death (12,28,29), T-cell-targeted deletion of both STIM1 and STIM2 leads to autoimmune symptoms. Decreased numbers of Tregs as well as compromised suppressive function of Tregs on effector T cells were noted in these mice, suggesting that Treg development appears to be especially sensitive to the absence of STIM-dependent Ca 2+ influx (12).…”

“…Whereas global deletion of Orai1, STIM1, or STIM2 in mice results in premature death (12,28,29), T-cell-targeted deletion of both STIM1 and STIM2 leads to autoimmune symptoms. Decreased numbers of Tregs as well as compromised suppressive function of Tregs on effector T cells were noted in these mice, suggesting that Treg development appears to be especially sensitive to the absence of STIM-dependent Ca 2+ influx (12). It also has been demonstrated that calcineurin-NFAT signaling, which is activated by Ca 2+ entry via SOCE channels, is important for regulating Treg development and function (30,31).…”

“…Thus, Orai-STIM-dependent Ca 2+ signaling has a dominant role in the maintenance of immune balance. In a mouse model with T-lymphocyte-targeted deletion of STIM1 and STIM2, SOCE and SOCE-dependent cytokine production were severely attenuated, along with a substantial decrease in the number and function of regulatory T cells (Tregs) (12). These mice displayed signs of autoimmunity, including dermatitis, blepharitis, and lymphoproliferation, with significant splenomegaly and infiltration of lymphocytes into epithelial tissues, such as liver and lungs.…”

STIM2 regulates AMPA receptor trafficking and plasticity at hippocampal synapses

“…Stim2 fl/fl mice 25 were crossed to B6.Cg-Tg(CaMKII-Cre)T29-1Stl/J mice 26 Wilcoxon signed rank test was used for within group comparisons and Mann-Whitney-U-test, when compared between groups. Statistical significance was assumed at p < 0.05.…”

Store-Operated Calcium Channels: New Perspectives on Mechanism and Function

“…These findings have triggered intense interest in developing specific pharmacologic inhibitors of the CRAC channel to treat a variety of autoimmune disorders. In mice, the absence of Orai1 or STIM1 function causes multiple defects of cytokine expression in T cells (interleukin (IL)-2, interferon-g, IL-4, IL-10) Oh-Hora et al 2008), and in mast cells, defective synthesis or release of inflammatory mediators (tumor necrosis factor-a, IL-6, serotonin, and leukotriene C 4 ) leads to a reduced anaphylaxis response in vivo (Baba et al 2008;Vig et al 2008). B-cell targeted deletion of STIM1 and STIM2 revealed a novel role for SOCE in enabling B cells to limit autoimmunity; in these animals reduced secretion of the anti-inflammatory cytokine IL-10 was linked to increased severity of experimental autoimmune encephalomyelitis, a model for multiple sclerosis (Matsumoto et al 2011).…”