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 (
STIM
1) and its activation of the Ca
2+
channel
ORAI
1. We here identify patients with a novel mutation in
STIM
1 (p.L374P) that abolished Ca
2+
influx and resulted in increased susceptibility to fungal and other infections. In mice, deletion of
STIM
1 in all immune cells enhanced susceptibility to mucosal
C. albicans
infection, whereas T cell‐specific deletion of
STIM
1 impaired immunity to systemic
C. albicans
infection.
STIM
1 deletion impaired the production of Th17 cytokines essential for antifungal immunity and compromised the expression of genes in several metabolic pathways including Foxo and
HIF
1α signaling that regulate glycolysis and oxidative phosphorylation (
OXPHOS
). Our study further revealed distinct roles of
STIM
1 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.
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