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

## TL;DR

This study shows that the AMPA receptor in T cells limits immune suppression and that its deletion protects against autoimmune disease by promoting regulatory T cell development.

## Contribution

The first functional characterization of AMPAR-deficient T cells and their role in promoting regulatory T cell differentiation and immune suppression.

## Key findings

- AMPAR deletion in T cells protects against autoimmune neuroinflammation in an EAE model.
- AMPAR deficiency promotes Treg differentiation and enhances IL2/STAT5 signaling and metabolic pathways.
- Blocking AMPARs on T cells could be a novel therapeutic strategy for autoimmune diseases.

## Abstract

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 CD4Cre 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. In vitro 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.

•AMPAR deletion in T cells or blockade protects against autoimmune neuroinflammation•Loss of AMPAR signaling promotes inducible Treg (iTreg) differentiation•AMPAR deficiency enhanced IL2/STAT5 signaling, glycolysis, and lipid synthesis

AMPAR deletion in T cells or blockade protects against autoimmune neuroinflammation

Loss of AMPAR signaling promotes inducible Treg (iTreg) differentiation

AMPAR deficiency enhanced IL2/STAT5 signaling, glycolysis, and lipid synthesis

Immunology; Immune system; Immune response; Stem cells research