The ionotropic AMPA receptor contributes to autoimmunity via altered regulatory T cell differentiation

The AMPA receptor (AMPAR) is an ionotropic glutamate receptor that is essential for neuronal communication, yet its role in the immune system remains poorly understood. Here, using a <i>CD4Cre</i> selective deletion mouse model, we provide the first functional characterization of AMPAR deficient T cells. We demonstrate that AMPAR deletion in T cells significantly protects against severe paralysis in an experimental autoimmune encephalomyelitis (EAE) model, and this protection is associated with increased regulatory T cell (Treg) presence within the spinal cord. <i>In vitro</i> studies reveal that the deletion of the AMPAR intrinsically promotes Treg generation. Mechanistically, AMPAR deletion increases IL2 signaling and activates the mTORC1 pathway, supporting Treg development and function. These novel findings suggest that a function of the AMPAR in CD4 T cells is to limit immune suppression by restricting Treg differentiation. Targeting AMPARs on T cells could offer a novel therapeutic approach for the treatment of autoimmune disease.