The role of ionotropic AMPA receptors in T cell tolerance

The ability of T cells to mount effective immune responses to pathogens and cancer while remaining tolerant to self-tissue is critical for maintaining immune homeostasis. Previously, our group identified neuritin, a neuronal protein, as a highly differentially expressed gene in anergic and regulatory T cells. Furthermore, our results indicate neuritin deficient mice exhibit enhanced autoimmunity due, in part, to dysfunctional regulatory T cells. Neuritin was recently identified as an accessory component of the ionotropic AMPA receptor (AMPAR) complex in neurons. AMPAR complexes are typically found on the post-synaptic neuronal cell and mediate glutamate dependent cation flux. Given our previous findings involving neuritin in autoimmunity and this newly identified interaction between neuritin and AMPAR, we sought to evaluate whether there is a role for the AMPAR in T cell tolerance. Here, we show that the AMPAR is expressed in CD4+ T cells and that the specific deletion of the AMPAR in T cells (AMPAR KO) leads to significantly reduced disease pathogenesis in an experimental autoimmune encephalomyelitis (EAE) model. The spinal cord inflammatory immune infiltrates from AMPAR KO mice are markedly reduced in cell number, proliferative state, and expression of proinflammatory cytokines compared to wild type (WT) mice. In addition, we have observed an increase in the CD4+FoxP3+ regulatory cell population among spinal cord infiltrates from AMPAR KO EAE mice. Consistent with the EAE model, AMPAR KO T cells also exhibit increased induced regulatory T cell development during in vitro differentiation. Taken together our results support a previously unappreciated role for ionotropic AMPA receptors in regulating T cell tolerance.