STIM1-mediated calcium influx controls antifungal immunity and the metabolic function of non-pathogenic Th17 cells.

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+)channelORAI1. We here identify patients with a novel mutation inSTIM1 (p.L374P) that abolished Ca(2+)influx and resulted in increased susceptibility to fungal and other infections. In mice, deletion ofSTIM1 in all immune cells enhanced susceptibility to mucosalC. albicansinfection, whereas T cell-specific deletion ofSTIM1 impaired immunity to systemicC. albicansinfection.STIM1 deletion impaired the production of Th17 cytokines essential for antifungal immunity and compromised the expression of genes in several metabolic pathways including Foxo andHIF1 alpha signaling that regulate glycolysis and oxidative phosphorylation (OXPHOS). Our study further revealed distinct roles ofSTIM1 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.