STIM1‐mediated calcium influx controls antifungal immunity and the metabolic function of non‐pathogenic Th17 cells. Issue 8 (1st July 2020) - Kahlfuss, Sascha
Abstract: 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. 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.