Glycolysis gene Hif1a negatively regulates the induction of intraepithelial CD4+CD8aa+ T cells

Abstract

Abstract Intestinal CD4 T cells reside in both lamina propria and intraepithelial lesion. We previously reported CD4+CD8aa+ intraepithelial lymphocytes (DPIELs) exhibit anti-inflammatory function against intestinal inflammation. Recently, metabolic status is important both for induction and for keeping cells in active phase. For example, Tregs use oxphos for cellular metabolism, while Th17 cells mainly use glycolysis. It is still unknown the metabolic status in tissue resident T cells and the effect of metabolic related gene for cell development in gut. By using mito-tracker and seahorse system, we first evaluated the metabolic status of tissue resident CD4 T cells. Then we used mouse model by deletion of the glycolysis related gene to uncover the development of intestinal resident CD4 T cells. The ratio of mitochondrial membrane potentialhipopulation of CD4IELs was increased in Germ free mice than in SPF mice. Most of DPIELs express the mitochondira membrane potentiallo. Although total CD4 positive IELs increased glycolysis compared to the splenic naive CD4 T cells, DPIELs expressed less pS6 and reduced glycolysis related gene, Hif1a. Next, We generated conditional Hif1a and Vhl ko mice (CD4cre: Hif1af/f: Hif1a (ΔCD4), CD4cre: Vhlf/f: Vhl (ΔCD4), CD4cre: Hif1af/f: Vhlf/f (DKO)) respectively to understand whether Hif1 was negatively regulated the induction of DPIELs or not. The ratio of DPIELs was increased in Hif1a (ΔCD4), DKO mice and decreased in Vhl (ΔCD4) mice. These results reveal total CD4IELs uses preferentially glycolysis, but glycolytic related gene Hif1a is negatively regulated the induction of DPIELs.