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Immunity to fungal infections is mediated by cells of the innate and adaptive immune system including Th17 cells. Ca 2+ influx in immune cells is regulated by stromal interaction molecule 1 (STIM1) and its activation of the Ca 2+ channel ORAI1. We here identify patients with a novel mutation in STIM1 (p.L374P) that abolished Ca 2+ influx and resulted in increased susceptibility to fungal and other infections. In mice, deletion of STIM1 in all immune cells enhanced susceptibility to mucosal C. albicans infection, whereas T cell‐specific deletion of STIM1 impaired immunity to systemic C. albicans infection. STIM1 deletion impaired the production of Th17 cytokines essential for antifungal immunity and compromised the expression of genes in several metabolic pathways including Foxo and HIF1α signaling that regulate glycolysis and oxidative phosphorylation (OXPHOS). Our study further revealed distinct roles of STIM1 in regulating transcription and metabolic programs in non‐pathogenic Th17 cells compared to pathogenic, proinflammatory Th17 cells, a finding that may potentially be exploited for the treatment of Th17 cell‐mediated inflammatory diseases. Synopsis Pathogenic Th17 cells have been implicated in autoimmune diseases, while non‐pathogenic Th17 cells provide immunity to fungal pathogens. Patients with mutations in ORAI1 or STIM1 have impaired Ca 2+ signaling in immune cells and are more susceptible to infections with fungal pathogens. A novel missense mutation in STIM1 (p.L374P) abolishes Ca 2+ signals in immune cells by interfering with the activation of ORAI1, the pore‐forming subunit of the calcium release‐activated calcium (CRAC) channel. T cells of patients with STIM1 p.L374P mutation fail to produce cytokines when challenged with C. albicans and have severe defects in metabolic functions including glycolysis and oxidative phosphorylation (OXPHOS). Deletion of STIM1 and its homologue STIM2 in all immune cells results in enhanced severity of mucosal C. albicans infection, which is associated with defective T cell and neutrophil function. T cell‐specific deletion of STIM1 reduces resistance to systemic C. albicans infection and is associated with impaired effector functions of Th1 and non‐pathogenic Th17 cells. STIM1 is required for the transcriptional regulation of aerobic glycolysis and OXPHOS in non‐pathogenic Th17 cells, whereas glycolysis in pathogenic Th17 cells is independent of STIM1 and CRAC channel function. Graphical Abstract Pathogenic Th17 cells have been implicated in autoimmune diseases, while non‐pathogenic Th17 cells provide immunity to fungal pathogens. Patients with mutations in ORAI1 or STIM1 have impaired Ca 2+ signaling in immune cells and are more susceptible to infections with fungal pathogens.

Stromal interaction molecule 1 (STIM1) is critical for store-operated Ca 2+ entry (SOCE) and T cell activation. T helper 1 (T H 1) cells, which express T-bet (encoded by TBX21 ), mediate immunity to intracellular pathogens. Although SOCE is known to regulate other T H lineages, its role in Th1 differentiation remains unclear. Here, we report a patient with an intronic loss-of-function mutation in STIM1 , which abolishes SOCE and causes immunodeficiency. We demonstrate that SOCE promotes nuclear factor of activated T cells (NFAT) binding to conserved noncoding sequence (CNS)-12 in the TBX21 enhancer and enables NFAT to synergize with STAT1 to mediate TBX21 expression. While SOCE-deficient CD4 + T cells have reduced expression of TBX21 in the absence of interleukin-12 (IL-12), their expression of IL-12 receptors β1 and β2 is increased, sensitizing them to IL-12 signaling and allowing IL-12 to rescue T-bet expression. Our study reveals that the STIM1-SOCE–NFAT signaling axis is essential for the differentiation of Th1 cells depending on the cytokine milieu. Feske and colleagues show how STIM- and ORAI-dependent calcium activation of NFAT plus IFN–STAT1 signaling activates T-bet expression independently of IL-12 stimulation. This NFAT–STAT1 activation pathway is required for T H 1 cell differentiation and protection against viral infections when IL-12 is missing.

Objectives. Sjögren's Disease (SjD) is an autoimmune disorder characterized by progressive dysfunction, inflammation and destruction of salivary and lacrimal glands, and by extraglandular manifestations. Its etiology and pathophysiology remain incompletely understood, though a role for autoreactive B cells has been considered key. Here, we investigated the role of effector and regulatory T cells in the pathogenesis of SjD. Methods. Histological analysis, RNA-sequencing and flow cytometry were conducted on glands, lungs, eyes and lymphoid tissues of mice with regulatory T cell-specific deletion of stromal interaction proteins (STIM) 1 and 2 (Stim1/2Foxp3), which play key roles in calcium signaling and T cell function. The pathogenicity of T cells from Stim1/2Foxp3 mice was investigated through adoptively transfer into lymphopenic host mice. Additionally, single-cell transcriptomic analysis was performed on peripheral blood mononuclear cells (PBMCs) of patients with SjD and control subjects. Results. Stim1/2Foxp3 mice develop a severe SjD-like disorder including salivary gland (SG) and lacrimal gland (LG) inflammation and dysfunction, autoantibodies and extraglandular symptoms. SG inflammation in Stim1/2Foxp3 mice is characterized by T and B cell infiltration, and transcriptionally by a Th1 immune response that correlates strongly with the dysregulation observed in patients with SjD. Adoptive transfer of effector T cells from Stim1/2Foxp3 mice demonstrates that the SjD-like disease is driven by interferon (IFN)-γ producing autoreactive CD4+ T cells independently of B cells and autoantiboodies. scRNA-seq analysis identifies increased Th1 responses and attenuated memory Treg function in PBMCs of patients with SjD. Conclusions. We report a more accurate mouse model of SjD while providing evidence for a critical role of Treg cells and IFN-γ producing Th1 cells in the pathogenesis of SjD, which may be effective targets for therapy.Competing Interest StatementS.F. is a scientific cofounder and consultant of Calcimedica. None of the other authors has competing interests.

Stromal interaction molecule 1 (STIM1) is critical for store-operated Ca entry (SOCE) and T cell activation. T helper 1 (T 1) cells, which express T-bet (encoded by TBX21), mediate immunity to intracellular pathogens. Although SOCE is known to regulate other T lineages, its role in Th1 differentiation remains unclear. Here, we report a patient with an intronic loss-of-function mutation in STIM1, which abolishes SOCE and causes immunodeficiency. We demonstrate that SOCE promotes nuclear factor of activated T cells (NFAT) binding to conserved noncoding sequence (CNS)-12 in the TBX21 enhancer and enables NFAT to synergize with STAT1 to mediate TBX21 expression. While SOCE-deficient CD4 T cells have reduced expression of TBX21 in the absence of interleukin-12 (IL-12), their expression of IL-12 receptors β1 and β2 is increased, sensitizing them to IL-12 signaling and allowing IL-12 to rescue T-bet expression. Our study reveals that the STIM1-SOCE-NFAT signaling axis is essential for the differentiation of Th1 cells depending on the cytokine milieu.