This application is focused on understanding the molecular mechanisms underlying reprogramming of lipid metabolism in CD4 T helper subsets, and assessing the impact of sterol metabolism on T helper cell function. Accumulating evidence indicates that CD4 T helper cells rapidly change their metabolic state in response to TCR activation and cytokine signals. This reprogramming is necessary to match the bioenergetic and biosynthetic requirements of specific effector functions. In general pro-inflammatory CD4 T cells (e.g., Th1 and Th17) acquire a robust glycolytic program, and shift their metabolism towards an anabolic state. In contrast, regulatory T cells are largely reliant on fatty acid oxidation and macromolecule catabolism to meet their bioenergetic and biosynthetic requirements. This distinction in metabolic programming appears to be essential for proper T helper cell function. Genetic or pharmacologic manipulation of a T helper cell's metabolic state can attenuate or exacerbate specific effector functions. For example, enforcing a glycolytic program perturbs the suppressive ability of Tregs, and results in a loss of self-tolerance in models systems. In contrast, enforcing fatty acid oxidative metabolism downregulates the pro-inflammatory function of Th1 and Th17 cells, thereby attenuating disease pathogenesis. These observations have led to the concept that a CD4 T helper cells metabolic state is a fundamental component of the effector program. Despite the clear importance of acquiring and maintaining the appropriate metabolic state, the molecular mechanisms underlying how distinct T helper cells acquire the requisite metabolic programs remain poorly understood. In recent work we have identified the sterol regulatory element binding proteins (SREBP1 and 2) as critical regulators of metabolic reprogramming in CD8 T cells. Mechanistic studies revealed that SREBPs are activated by TCR signals and drive acquisition of glycolysis and anabolic metabolism. In the absence of SREBP activity, we found that CD8 T cells were unable to upregulate glycolytic flux and synthesis of lipids, resulting in poor proliferative capacity and attenuated effector responses. These data have led us to hypothesize that SREBPs would play a critical function in regulating the CD4 T helper subset differentiation and effector function. In support of this hypothesis, we find in preliminary data that attenuation of the SREBP program selectively perturbs the in vitro differentiation of Th1 and Th17 cells, but does not influence induction of regulatory T cells, nor does it influence the generation/homeostasis of Foxp3-positive Tregs in vivo. Thus, we conclude that SREBP signaling plays an important and previously undefined role in controlling the balance of T helper subsets. In this application, we extend on these intriguing preliminary data and propose three integrated aims designed to elucidate the molecular mechanism(s) by which SREBPs influence T helper cell function, and determine if these metabolic pathways control the balance between self-tolerance and autoimmunity.
A major goal of the immunology infectious disease and rheumatology communities is defining the signals that shape how the immune system responds to pathogens while maintaining self-tolerance. In this application, we examine the recently uncovered cross talk between cholesterol metabolism and the differentiation of CD4 T helper subsets. These studies will provide mechanistic insights as to how lipid metabolism regulates adaptive immunity.