Glutaminase-mediated glutamate metabolism is critical for maintaining Th17/Treg balance

Autoimmune diseases are severe disorders that affect populations worldwide. Their occurrence is considered to be multifactorial: genetic, hormonal and immunological factors all contribute to the development of autoimmune diseases. CD4 T cells differentiate into different subtypes, among which Th17 and Treg cells are the two most important in regulation of immune response balance. The Th17/Treg equilibrium is crucial in the pathogenesis of autoimmune diseases. Glutamate, an excitatory neurotransmitter in the nervous system, induces multiple effects. It activates normal T cells, enhancing cell adhesion, migration, secretion and gene expression. However, the effect of glutamate on T cell fate remains unclear. Here, we found that glutamate promotes Treg differentiation but suppresses Th17 differentiation. Further results showed that the rate-limiting enzyme of glutamate metabolism, glutaminase (GLS), is the key regulator for Treg cell generation. These findings suggest that GLS-mediated glutamate metabolism is critical for Treg cell differentiation, and may represent a potential therapeutic target for autoimmune disease.