MECHANISTIC STUDY OF TGF-BETA DEPENDENT CONTROL OF GUT RESIDENT MEMORY T CELLS

Infectious diseases pose a significant public health burden, accounting for nearly one-fifth of deaths globallyper annum. Most infections are initiated from a restricted mucosal tissue, such as the intestine. To fightintestinal infections, gut-resident immune cells are superior to circulating ones. There is a surge of recentinterest in tissue-resident memory T (TRM) cells that have been shown to be a critical adaptive immunecomponent of mucosal immunity. These cells have been flagged as an ideal cell population to be generated inT cell-based vaccines. However, the factors involved in the differentiation and maintenance of gut TRM cellsremain poorly defined.Distinct from other T cell populations in the periphery, gut TRM cells harbor a unique transcription network. Wepropose that simultaneously suppressing the transcription factor Eomes and inducing the transcription factorRunx3 are required for the proper differentiation and maintenance of gut TRM cells following acute infections.Based on our previous findings, we hypothesize that TGF-? mediates TRM cell differentiation and maintenancein the gut through controlling Eomes- and Runx3-dependent transcription programs. Eomes and Runx3 arerelatively independent nodules downstream of TGF-? signaling in gut TRM cells. Using different genetic models(conditional and inducible knockout mice that specifically delete TGF-? receptor on T cells, and TGF-?receptor/Eomes double conditional knockout mice in T cells), three major questions will be addressed: 1) When do gut TRM precursor or gut TRM cells receive TGF-? signaling? Whether continuous TGF-? signaling is required for the maintenance of gut TRM cells? What is the transcription program maintained by TGF-? signaling in gut TRM cells? 2) What is the function of TGF-?-dependent down-regulation of transcription factor Eomes in the differentiation and maintenance of gut TRM cells? What is the TGF-?-dependent transcription program that is prevented by Eomes in gut TRM cells? 3) What are the functions of TGF-? dependent induction of transcription factor Runx3? Whether Eomes and Runx3 together control the majority of TGF-?-dependent transcription program in gut TRM cells?The results from these studies will elucidate the transcription program underlying TGF-?-controlleddifferentiation and maintenance of gut TRM cells. These studies will substantially further our understanding ofgut TRM cell biology and lay the basis for future translational works.