SHMT2 Regulates T Cell Homeostasis and Mucosal Inflammation Via Metabolic and Lipid Remodeling 2256280

Abstract Introduction Serine hydroxymethyltransferase 2 (SHMT2) is a mitochondrial enzyme essential for one-carbon metabolism, nucleotide biosynthesis and redox balance supporting cell proliferation and survival. While SHMT2 is required for the effector CD8+T cells expansion following infection, its role in CD4+T cell development, differentiation and Treg function under inflammatory conditions remains undefined. Methods We generated T cell-specific (Shmt2fl/flCD4Cre) and Treg-specific (Shmt2fl/flFoxp3YFPCre) conditional knockout (cKO) mice. T cell developmental and homeostatic phenotype were characterized by flow cytometry, and Th subset differentiation was assessed in vitro and in vivo, while Treg function was tested using naïve CD4+ T cell transfer in Rag⁻/⁻ recipients. Untargeted metabolomics and lipidomics were performed by mass spectrometry. Results SHMT2-deficient T cells developed normally in the thymus but displayed CD44high memory-like phenotype at the periphery. SHMT2 deletion in T cells impaired Th1, Th2, and Th17 differentiation, whereas induced Treg development remained unaffected. Upon house dust mite challenge, Shmt2CD4-cKO mice exhibited reduced eosinophilia, Th2 cytokines and serum IgE. In contrast, Shmt2Treg-cKO mice showed elevated lung infiltration of eosinophils, neutrophils, and T cells, with increased Th2/Th17 cytokines and serum IgE. Despite increased Treg frequencies, Shmt2Treg-cKO Tregs failed to suppress mucosal inflammation in Rag-/- mice, suggesting that SHMT2 is dispensable for Treg development but required for Treg suppressive function. The loss of SHMT2 in T cells disrupted mitochondrial one-carbon metabolism, induced redox imbalance and enhanced neutral lipid storage and phospholipid synthesis, with compensatory arginine-proline upregulation and taurine depletion to sustain survival under oxidative stress. Conclusion SHMT2 maintains T cells metabolic fitness and Treg regulatory function, highlighting SHMT2-dependent metabolic pathways as a therapeutic target in mucosal inflammation. Funding Source 2024 Hevolution/AFAR New Investigator Award Topic Categories Mucosal and Regional Immunology (MUC)