Intracellular 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.