A New Therapeutic Strategy for Multiple Sclerosis: DRAK2 Inhibition Promotes Induction of Regulatory T Cells via Metabolic Reprogramming 2256515

Abstract Introduction Multiple Sclerosis (MS) is an autoimmune disease where autoreactive T cells cause damage in 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. This suggests that DRAK2 inhibition suppresses autoreactive T cells in mice. Methods T cell activation, PBMC isolation from whole blood, flow cytometry, cell staining for confocal imaging, LC-MS for metabolomics, western blotting. Results Drak2-/- T cells induced higher Treg numbers upon activation, and mouse in vivo data suggests that EAE resistance in Drak2-/- mice is due to higher number of Tregs suppressing inflammation that can lead to autoimmunity. DRAK2 deficiency also resulted in higher oxidation of cellular lipids, which is connected to its higher autophagic flux. Our studies have shown that Drak2-/- T cells undergo faster beta oxidation, which affects TCR signaling that eventually favors AMPK signaling over mTOR signaling for T cell expansion. Newly synthesized DRAK2 inhibitors exhibited promising results with Treg induction accompanied by a decrease in cellular lipid contents in both mouse and human T cells upon T cell activation. Remarkably, T cells from MS patients also showed Treg induction followed by DRAK2 inhibitor treatment, with altered metabolic signatures. Conclusion Altogether, the results of DRAK2 studies demonstrate that DRAK2 regulates metabolic signals to determine T cell fate. Further studies on how DRAK2 regulates T cell metabolism may offer new insights to understand T cell differentiation and homeostasis. If DRAK2 inhibitors can induce a significant number of suppressive Tregs that can successfully target autoreactive T cells, it will offer a new avenue on a future MS therapeutics development. Funding Source NIND/NIH - T32 Training Program in Stem Cell Translational Medicine for Neurological Disorders Topic Categories Therapeutic Approaches to Autoimmunity (THER)