Dysregulated immune responses against our own normal tissues result in autoimmunity, an often chronic, debilitating, and life-threatening group of diseases. Traditional approaches in treatment involve the deliberate induction of broad immunosuppression, which undoubtedly exposes the body to a higher risk of infection. An alternative approach would be to disrupt key steps during differentiation of selected T cell subsets, in order to offer a targeted immunosuppressive treatment. Investigating T cell differentiation in the pathogenesis and treatment of autoimmune diseases can be approached in a two-fold manner. Inflammatory T cells, specifically the Th17 subset, are a main driver in the pathogenesis of autoimmune disease, including multiple sclerosis, psoriasis, and colitis. On the opposing axis lie regulatory T cells, which modulate the immune system by maintaining tolerance to self-antigens and suppressing effector T cell proliferation.
The ability of naïve T cells to proliferate and differentiate into effector T cells depends on the mechanistic target of rapamycin (mTOR) pathway. The mTORC1 complex activates biosynthetic processes that are crucial to sustain T cell growth and effector function. The potent immunosuppressive drug rapamycin (RAP) strongly blocks CD4 T cell proliferation and effector differentiation, despite only partial inhibition of mTORC1. The ribosomal protein S6 kinase 1 and 2 are activated by mTORC1 and are highly RAP-sensitive. The first aim of this dissertation focuses on the role of S6K2 in Th17/Treg differentiation and function in autoimmunity.
Distinct metabolic processes separate the CD4+ effector subsets Th17 and Treg. The metabolic signature of inflammatory Th17 cells involves a high glycolytic capacity that requires de novo synthesis of fatty acids. Conversely suppressive Tregs rely on oxidative phosphorylation, which involves beta-oxidation of extracellularly obtained fatty acids. Acetyl-CoA Carboxylase, or ACC, is a master regulator of fatty acid synthesis and oxidation. Enzymatically active ACC catalyzes the irreversible carboxylation of acetyl-CoA to produce malonyl-CoA, which results in fatty acid biosynthesis and inhibition of beta-oxidation of fatty acids. Previous findings report Th17 cells to require ACC1 in their development, but that this isoform is dispensable for the induced Treg subset. Using a newly developed allosteric inhibitor of ACC1 and ACC2, the second aim of this dissertation is to evaluate the potential to target ACC enzymes using this novel inhibitor as a therapeutic strategy in the treatment of autoimmune diseases.