Metabolic targeting of CD4 T cells in CNS autoimmunity - PROJECT SUMMARY/ABSTRACT Inflammatory CD4 T helper (Th) cells are central to the pathogenesis of many autoimmune diseases— including multiple sclerosis (MS)—while Foxp3+ regulatory T (Treg) cells provide protection. Yet, major gaps remain in our understanding of how to selectively target pathogenic Th cells in autoimmune disease while limiting impact on Treg cells and other immune cells that mediate protective immunity and tissue repair. Metabolic reprogramming is a fundamental process underlying the fate and function of activated T cells. We have found that altering the metabolism of the amino acid methionine by lowering methionine levels in the diet slows the onset and progression of a mouse model of MS (experimental autoimmune encephalomyelitis, EAE), in part by limiting the presence and function of pathogenic CD4 Th cells in the central nervous system (CNS). Preliminary data from our laboratory has identified methionine adenosyltransferase 2A (MAT2A)the enzyme that synthesizes S-adenosylmethionine (SAM) from methionine—as the critical mediator downstream of methionine regulating CD4 T cell function. Here, we will apply genetic and pharmacologic tools (Mat2a conditional knockout mice and MAT2A inhibitors) to cell culture and animal models to determine how MAT2A controls CD4 T cell fate and function in the context of CNS autoimmunity. Defining how MAT2A differentially regulates pathogenic versus regulatory CD4 T cell function is crucial to understanding the metabolic regulation of CNS autoimmunity, and opens new avenues for treating autoimmunity by targeting biosynthesis of SAM. OBJECTIVE: to define the mechanisms by which MAT2A regulates the differentiation and function of pathogenic Th cells versus protective Treg cells to modulate neuroinflammation in the CNS. HYPOTHESIS: inhibiting MAT2A alters CD4 T cell function through effects on epigenetic programming, resulting in (a) reduced Th cell pathogenicity and neuroinflammation in EAE, as well as (b) enhanced development of suppressive Treg subsets that provide protection. SPECIFIC AIMS: (1) Determine how MAT2A differentially controls Th versus Treg cell differentiation, (2) Determine how MAT2A inhibition counters T cell-mediated CNS inflammation, (3) Establish how MAT2A epigenetically promotes Th versus Treg cell identity. IMPACT: The significance of this proposal is understanding how SAM directs CD4 T cells between pathogenic and protective states, with the potential to determine how inhibiting MAT2A can block or “retrain” pathogenic T cell responses and, thus, reduce CNS autoimmunity. We also expect to gain new mechanistic insight into how MAT2A influences Th and Treg cell programming by regulating chromatin modifications. This project will lay the essential groundwork for future basic discovery and translational studies with novel therapeutics targeting SAM metabolism to treat autoimmune diseases such as MS.
