In vivo genetic screening to target CD4 T cell metabolism in atherosclerosis

Atherosclerosis is the most common form of cardiovascular disease associated with increased circulating lipids and immune-mediated inflammation. Work by my group and others have demonstrated that atherosclerosis is driven, in part, by inflammatory CD4 T effector (Teff) cells. As many treatments for atherosclerosis which broadly target dyslipidemia are not enough to decrease disease burden, there is a need to identify new molecularly targeted therapeutic strategies to selectively inhibit inflammation. One strategy is to target inflammatory Teff or promote immune suppressive T cells (Treg). An unexplored path is identifying new and exploiting known metabolic regulators of CD4 T cell differentiation and activation. It is established from the work of Dr. Rathmell’s group (collaborator) that how T cells obtain and utilize nutrients is closely regulated and can exert profound influences on their function and fate. Specifically, inflammatory Teff and suppressive Treg utilize distinct sets of nutrients and metabolic pathways. Here we propose to examine a metabolic candidate, MTHFD2, as potential new therapeutic target for atherosclerosis and to also utilize a genetic approach to identify new classes of therapeutic targets. We propose to test whether T cell specific knockout of this enzyme, important in one-carbon metabolism and stabilization of regulatory T cells, plays a role in atherosclerosis.