biostudies-literatureUnknown25(4)Harada YIntestinal intraepithelial lymphocytes (IELs), the first line of defense against microbial and dietary antigens, are classified as natural or induced based on their origin and receptor expression. Induced CD4⁺CD8αα⁺TCRβ⁺ T cells (double positive, DP_IELs) originated from CD4⁺CD8α^-TCRβ⁺ T cells (single positive, SP_IELs) increase with aging. However, the metabolic requirements and the metabolic-related genes in IEL development remain unclear. We determined that the intraepithelial compartment is hypoxic in the presence of microbes and DP_IELs increased more than natural IELs in this location. Moreover, DP_IELs consumed less oxygen and glucose and exhibited unique alterations in mitochondria. Using inhibitors and genetically modified mice, we revealed that DP_IELs adapt to their surrounding oxygen-deprived environment in peripheral tissues by modulating specific genes, including hypoxia-inducible factor, mammalian target of rapamycin complexes (mTORC), phosphorylated ribosomal protein S6 (pS6), and other glycolytic factors. Our findings provide valuable insight into the metabolic properties of IELs.iScience104021https://www.ebi.ac.uk/biostudies/studies/S-EPMC8933710biostudies-literatureIntracellular metabolic adaptation of intraepithelial CD4⁺CD8αα⁺ T lymphocytes.PMC8933710Harada YSujino THirao AKanai TOgata HHosoe NKubota YTanemoto SYoshimatsu YNomura EMiyamoto KUmeda SMikami YNakamoto NTakabayashi KIkenoue TOno KfalseIntracellular metabolic adaptation of intraepithelial CD4⁺CD8αα⁺ T lymphocytes.Intestinal intraepithelial lymphocytes (IELs), the first line of defense against microbial and dietary antigens, are classified as natural or induced based on their origin and receptor expression. Induced CD4⁺CD8αα⁺TCRβ⁺ T cells (double positive, DP_IELs) originated from CD4⁺CD8α^-TCRβ⁺ T cells (single positive, SP_IELs) increase with aging. However, the metabolic requirements and the metabolic-related genes in IEL development remain unclear. We determined that the intraepithelial compartment is hypoxic in the presence of microbes and DP_IELs increased more than natural IELs in this location. Moreover, DP_IELs consumed less oxygen and glucose and exhibited unique alterations in mitochondria. Using inhibitors and genetically modified mice, we revealed that DP_IELs adapt to their surrounding oxygen-deprived environment in peripheral tissues by modulating specific genes, including hypoxia-inducible factor, mammalian target of rapamycin complexes (mTORC), phosphorylated ribosomal protein S6 (pS6), and other glycolytic factors. Our findings provide valuable insight into the metabolic properties of IELs.2022-01-01T00:00:00Z2022 Apr2025-04-05T14:43:32.242Z2025-04-05T14:43:32.242ZS-EPMC89337103531368910.1016/j.isci.2022.104021