Mercedes Rincon

Equity Interest - Non-publicly traded entity ( e.g., stock, stock option, or other ownership interest)

Metabolic Regulation of Caspases and Survival in T Cells

The survival of effector T cells to the memory state is of fundamental importance to protection from infection as well as in autoimmune disorders. IL-15 has been implicated in the pathogenesis of various autoimmune diseases such as rheumatoid arthritis, multiple sclerosis, ulcerative colitis, celiac syndrome, and psoriasis. IL- 15 also indues the inflammatory cytokines TNF-? and IL-1? and is important in homeostatic proliferation of T cells. It is now appreciated that augmented homeostatic proliferation may be a driving force in several autoimmune disorders. IL-15 also drives a metabolic state characterized by high oxidative phosphorylation and low glycolysis, and we observe that this is associated with low levels of caspase-3 activity due to its inactivation by S-nitrosylation. Regulation of active caspases in cycling T cells is paramount to understanding T cell survival during both homeostatic proliferation as well as during the generation of memory T cells. We have also identified a novel protein, MCJ as a regulator of Complex I activity in the electron transport chain, and hence of mitochondrial respiration. IL-15 silences MCJ expression. The significance of the proposed studies is that it links for the first time the cytokine environment to metabolism via MCJ, and regulation of effector caspase-3 as a major determinant of cell survival. It then applies this to human rheumatoid arthritis synovium. The study presents a focused series of experiments on the metabolic regulation of caspase-3 activity by IL-15 and applies this to a real human autoimmune disease. It also suggests potential therapeutic options in autoimmune disorders by regulating IL-15, MCJ, or metabolism.