T cell maintenance: molecular mediators of T cell differentiation and survival

SUMMARY CD8 T cells play a key role in the elimination of intracellular infections and malignant cells and can provide long- lived protective immunity. In the response to infection, CD8 T cell metabolism is coupled to transcriptional, translational, and epigenetic changes that are driven by extracellular metabolites and immunological signals. These programs facilitate the adaptation of CD8 T cells to diverse and dynamic metabolic environments encountered in circulation and tissues. Defining the metabolic adaptations of CD8 T cells to specific tissue environments informs our understanding of how these cells protect against pathogens and tumors and maintain function at tissue barrier sites. Following the resolution of infection, a portion of effector CD8 T cells differentiate into long-lived memory CD8 T cells that either recirculate or establish long-lived tissue-resident memory T cells (TRM). Lodged in tissues throughout the body, CD8 TRM make up a significant portion of the T cell arsenal against reinfection and tumorigenesis. TRM adaptation is of special relevance at tissue-barrier sites, such as the small intestine (SI), where exposure to the microbiome, opportunistic pathogens, and diverse as well as fluctuant amounts of nutrients possible. However, the functional metabolic adaptations of T cells to tissue residency, including any variations between tissue types, are only beginning to be understood. We have found that TRM undergo tissue- specific metabolic adaptations and highlight the cholesterol biosynthetic pathway, and Srebp2, a key transcriptional regulator of cholesterogenesis to be of special relevance for SI-TRM formation. Based on these preliminary data, we hypothesize that the sustained induction of the cholesterol biosynthetic pathway is a key adaptation by SI TRM and that understanding the basis for this dependence will shed light on memory T cell homeostasis. We propose to: Aim 1) Investigate the role of Srebp2 in differentiation and homeostasis of effector and memory T cell populations and to uncover the relevant intermediates and products of this pathway for TRM, and Aim 2) Place Srebp2 in the transcriptional network that drives SI TRM and establish the impact of known SI TRM-inducing tissue cues on Srebp2 expression. Results from these studies will be crucial to the understanding of how CD8 T cell fate and function are mechanistically connected to their metabolism and will help design therapeutic approaches that harness the beneficial actions of CD8 T cells.