A new emerging target for treating multiple sclerosis: DRAK2 deficiency remodels lipid and cholesterol composition to favor Treg expansion 4779

Abstract Description Multiple sclerosis (MS) is an autoimmune disease where autoreactive T cells attack the central nervous system. Current therapies make patients vulnerable to infection and cancer during treatment, emphasizing the need for safer approaches. Previous study shows that DAP kinase-related apoptosis-inducing protein kinase 2 (DRAK2)-deficient mice are resistant to experimental autoimmune encephalomyelitis (EAE) without any defect in T cell recruitment to CNS upon infection. Drak2-/- T cells show increased Treg numbers upon activation, and mouse in vivo data demonstrates that the increased number of Treg is responsible for EAE resistance in Drak2-/- mice. Notably, upon T cell activation in vitro, effector T cell differentiation was interrupted in Drak2-/- T cells, potentially due to metabolic remodeling triggered by DRAK2 deficiency. Moreover, lipid staining and GC-MS on T cells revealed that there are huge differences in lipid and cholesterol composition in WT vs Drak2-/- T cells. Drak2-/- T cells also showed increased lipid oxidation presumably caused by higher autophagic flux, with lower Tripartite Motif containing 5 (TRIM5) protein levels in Drak2-/- T cells. Newly synthesized DRAK2 inhibitors show promising results with a decrease in lipid content with increased Treg numbers upon treatment in vitro. Further studies on DRAK2 will provide a deeper understanding in T cell metabolism and an innovative insight to develop safer and effective therapeutics for MS. Funding Sources T32 NS082174 Topic Categories Basic Autoimmunity (BA)