Na influx Orai1 inhibits intracellular ATP-induced mTORC2 signaling to disrupt CD4 T cell gene expression and differentiation.

T cell effector functions require sustained calcium influx. However, the signaling and phenotypic consequences of non-specific sodium permeation calcium channels remain unknown. α-SNAP is a crucial component of Orai1 channels, and its depletion disrupts the functional assembly of Orai1 multimers. Here we show that α-SNAP hypomorph, hydrocephalus with hopping gait, mice harbor significant defects in CD4 T cell gene expression and Foxp3 regulatory T cell (Treg) differentiation. Mechanistically, TCR stimulation induced rapid sodium influx in CD4 T cells, which reduced intracellular ATP, [ATP]. Depletion of [ATP] inhibited mTORC2 dependent NFκB activation in cells but ablation of Orai1 restored it. Remarkably, TCR stimulation in the presence of monensin phenocopied the defects in signaling and Treg differentiation, but not IL-2 expression. Thus, non-specific sodium influx bonafide calcium channels disrupts unexpected signaling nodes and may provide mechanistic insights into some divergent phenotypes associated with Orai1 function.