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.