Temporal CRAC channel blockade modulates the MYC-MXD axis to attenuate autoimmune inflammation

Effector T cell pathogenicity is strongly associated with the progression and severity of autoimmune diseases. Th17 cells are dependent on Ca²⁺ signaling mediated by the Ca²⁺ release-activated Ca²⁺ (CRAC) channels for their effector function. Here, we demonstrate that Th17 cells are uniquely sensitive to temporal inhibition of CRAC channels. Temporal CRAC channel block disturbed the effector functions and metabolic programming of Th17 cells, which were rescued by MYC expression. We uncovered a regulatory hierarchy in which CRAC channel activity during differentiation maintains MYC function by repressing Mxd genes, which antagonize MYC. In an animal model of autoimmunity, temporal CRAC channel block increased MXD expression to attenuate Th17 pathogenicity. These observations extend to human Th17 cells, where temporal CRAC channel blockade also impacts the MYC-MXD axis to impede cytokine production. Collectively, our study identifies a role for CRAC channels in regulating the MYC-MXD balance that governs Th17 effector function.