Na⁺ influx <i>via</i> Orai1 inhibits intracellular ATP-induced mTORC2 signaling to disrupt CD4 T cell gene expression and differentiation.

Abstract

T cell effector functions require sustained calcium influx. However, the signaling and phenotypic consequences of non-specific sodium permeation <i>via</i> 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, <i>Napa^hyh/hyh</i> 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 <i>Napa^hyh/hyh</i> CD4 T cells, which reduced intracellular ATP, [ATP]_i. Depletion of [ATP]_i inhibited mTORC2 dependent NFκB activation in <i>Napa^hyh/hyh</i> cells but ablation of Orai1 restored it. Remarkably, TCR stimulation in the presence of monensin phenocopied the defects in <i>Napa^hyh/hyh</i> signaling and Treg differentiation, but not IL-2 expression. Thus, non-specific sodium influx <i>via</i> bonafide calcium channels disrupts unexpected signaling nodes and may provide mechanistic insights into some divergent phenotypes associated with Orai1 function.