Global lactylome reveals lactylation-dependent mechanisms underlying T17 differentiation in experimental autoimmune uveitis.

Dysregulation of CD4 T cell differentiation is linked to autoimmune diseases. Metabolic reprogramming from oxidative phosphorylation to glycolysis and accumulation of lactate are involved in this process. However, the underlying mechanisms remain unclear. Our study showed that lactate-derived lactylation regulated CD4 T cell differentiation. Lactylation levels in CD4 T cells increased with the progression of experimental autoimmune uveitis (EAU). Inhibition of lactylation suppressed T17 differentiation and attenuated EAU inflammation. The global lactylome revealed the landscape of lactylated sites and proteins in the CD4 T cells of normal and EAU mice. Specifically, hyperlactylation of Ikzf1 at Lys promoted T17 differentiation by directly modulating the expression of T17-related genes, including Runx1, Tlr4, interleukin-2 (IL-2), and IL-4. Delactylation of Ikzf1 at Lys impaired T17 differentiation. These findings exemplify how glycolysis regulates the site specificity of protein lactylation to promote T17 differentiation and implicate Ikzf1 lactylation as a potential therapeutic target for autoimmune diseases.