Mitochondrial Membrane Dynamics in Th17 Cells

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PROJECT SUMMARY The extensive changes in phenotype and function observed in T cells upon activation are intimately linked to changes in cellular metabolism. The failure to engage specific and appropriate metabolic programs can impair or alter T cells, and thus lead to ineffective, or even overexuberant, immune responses. Central to metabolism are mitochondria, which serve as central hubs of energy generation and biosynthetic activity. Work from our group and others has provided mechanistic insights into how mitochondrial metabolism is critical to T cell differentiation and function. However, knowledge about why these organelles change shape to maintain metabolism, biosynthetic capacity, and function, and in what ways mitochondrial remodeling influences T cell activation, differentiation, or effector molecule expression is lacking. Investigating how dynamic changes in mitochondria regulate metabolism to impact CD4+ T cells will enhance our fundamental understanding of immunobiology and of how to manipulate these cells for disease therapy in the context of cancer, infection, and autoimmunity. In our initial experiments we found that unlike other Th cell subsets, Th17 cells, a cell type necessary for maintaining gut homeostasis and implicated in certain types of autoimmunity and inflammation, had elongated mitochondria in a fused network, as well as tight cristae morphology. These results suggested a differential role for mitochondrial fusion and the protein OPA1, which mediates both membrane fusion and cristae morphology, in these cells. OPA1 deletion had no discernible effect on Th1 and Th2 cell differentiation or cytokine production in vitro, and while Th17 cell differentiation was also unimpaired, IL-17 expression was drastically reduced. Further, mice with a T cell-specific OPA1 deletion were resistant to developing pathology in experimental autoimmune encephalomyelitis (EAE), a Th17 cell-mediated autoimmune disease of the central nervous system. Finally, our data revealed a role for liver kinase B1 (LKB1) in regulating the cellular response to OPA1-deficiency, and in restraining Th17 cell IL-17 expression when mitochondrial fusion is perturbed. In this proposal we now seek to understand how mitochondrial dynamics influence the function of diverse CD4+ T cell subsets. Our overall goal is to dissect the function of OPA1 in Th17 cell effector function, as well as probe its potential role other CD4+ T cell subsets, and to determine how MM fusion interfaces with LKB1 signaling to modulate cellular metabolism to limit IL-17 expression in settings of mitochondrial disruption or stress in vitro and in vivo. To this end, we propose to 1) explore the role of mitochondrial dynamics in CD4+ Th cells, 2) determine the extent to which LKB1 controls the cellular response to OPA1-deficiency in Th17 cells, and 3) investigate how metabolic changes upon disrupting mitochondrial fusion lead to dampened Th17 cell function.