Previous work from our lab and others has revealed that T cell development, once thought to be completed within the thymic microenvironment, continues for several weeks after cells have left the thymus and entered the lymphoid periphery. We have developed a model that allows unambiguous identification of the youngest peripheral T cells (recent thymic emigrants or RTEs) from mice that carry a GFP transgene driven by the RAG2 promoter. Using these reporter mice, which enable the retrieval of live, untouched RTEs from unmanipulated mice, we have shown that RTEs occupy a phenotypically and functionally distinct transitional T cell compartment. Compared to their mature counterparts, RTEs encountering antigen in the absence of inflammation exhibit diminished proliferation, reduced cytokine production, reduced expression of early activation markers, and increased expression of genes associated with dampened function or anergy. Based on solid preliminary data, we hypothesize that metabolic reprogramming, which accompanies and fuels the switch from quiescent to activated T cells, is altered in RTEs and serves as the mechanistic basis for their unique immune function. The goal of our proposed experiments is to test this novel hypothesis and to generate data that will serve as the foundation for a new direction of investigation in the field of RTE biology.
Our first aim i s to characterize the metabolic phenotype of RTEs by determining whether they have an altered metabolic function relative to mature T cells, comparing the metabolic profiles of resting and activated CD4 and CD8 RTEs and mature T cells, dissecting the signals responsible for altered metabolic reprogramming in RTEs, and determining whether RTEs and mature T cells differ in their capacity for exhaustion in the context of an anti- tumor response. Our second goal is to determine the relevance of altered metabolic reprogramming to the distinct function of RTEs by investigating whether cell-extrinsic factors correct RTE metabolism and function and dissecting the causal relationship between an altered metabolic profile and RTE function.
The youngest peripheral T cells, termed recent thymic emigrants, have dampened immune function. Preliminary data have pointed to altered metabolic reprogramming in RTEs as a potential driver of this immaturity. The goal of the proposed experiments is to elucidate the metabolic underpinnings of the differences in immune function that distinguish activated RTEs from their mature T cell counterparts.
|Cunningham, Cody A; Hoppins, Suzanne; Fink, Pamela J (2018) Cutting Edge: Glycolytic Metabolism and Mitochondrial Metabolism Are Uncoupled in Antigen-Activated CD8+ Recent Thymic Emigrants. J Immunol 201:1627-1632|
|Cunningham, Cody A; Helm, Eric Y; Fink, Pamela J (2018) Reinterpreting recent thymic emigrant function: defective or adaptive? Curr Opin Immunol 51:1-6|