Influence of metabolism in the regulation of T cell differentiation
Year: 2018
Type: dissertation
Abstract: Glucose is a key nutrient for T cells. Despite that T cell activation is impaired when they are deprived of glucose, it has also been shown that T effector responses can be elicited in vivo in glucose-poor environments, such as the intratumoral niche, which raises the question of how these cells can maintain their function in nutrient-restricted sites. In this work, we analyzed the ability of T effector cells to be activated by pro-inflammatory polarizing conditions under limiting glucose availability, using an in vitro model in which effector Th0 cells were restimulated to secondary effector T cells in glucose deficiency (0.3 mM). We found that secondary effector T cells could express characteristic Th1 and Th17 cytokines such as IL-17A and IFNγ when exposed to low glucose, but they lost expression of IL-22. Secondary effector T cells adapted to low glucose by reducing their rate of glucose consumption and expression of glycolysis genes, although they still kept using glucose as the main fuel for ATP production. In addition, we found that glucose limitation caused a mild, progressive impairment on mTORC1 activity in these cells that explained in part the downregulation of IL-22, an mTORC1-dependent cytokine. Our results also showed that secondary effector T cells that had experienced glucose stress acquired a nutrient-trained phenotype, and when they were later restimulated under glucose sufficiency they induced an altered cytokine expression pattern with exacerbated production of IL-22 and reduced IFNγ production. Finally, we observed that effector CD4+ T cells generated in different activation contexts in vivo exhibited different patterns of glucose-sensitive genes upon restimulation ex vivo, which suggested that the context in which T effector cells are induced might be a relevant determinant in shaping different response patterns to glucose limitation upon further stimulation. Altogether, our results uncover a previously unappreciated robustness of T cells to maintain effector function under nutrient-restricted conditions, also revealing that a prior history of nutrient stress can influence future effector T cell responses.
Authors: Tejedor Vaquero, Sonia Sonia
Language: English
Topic: T-cell and B-cell Immunology
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W2943675825