Depletion of extracellular asparagine impairs self-reactive T cells and ameliorates autoimmunity in a murine model of multiple sclerosis

Amino acids play critical roles in the activation and function of lymphocytes. Here we show that the non-essential amino acid, asparagine, is essential for optimal activation and proliferation of CD4⁺T cells. We demonstrate that asparagine depletion at different time points after CD4⁺T cell activation reduces mitochondrial membrane potential and function. Furthermore, asparagine depletion at specific time points during CD4⁺T cell differentiation reduces cytokine production in multiple CD4⁺T cell subsets. In an adoptive transfer model of experimental autoimmune encephalomyelitis (EAE), myelin oligodendrocyte-specific pathogenic T helper 17 cells differentiated under Asn-deficient conditions exhibited reduced encephalitogenic potential and attenuated EAE severity. In a model of EAE induced by active immunization, therapeutic depletion of extracellular Asn significantly reduced disease severity. These results identify asparagine as a key metabolic regulator of the pathogenicity of autoreactive CD4⁺T cells and suggest that targeting asparagine metabolism may be a novel therapeutic strategy for autoimmunity.