Intracellular metabolic adaptation of intraepithelial CD4+CD8αα+ T lymphocytes

Yosuke Harada, Tomohisa Sujino, Kentaro Miyamoto, Ena Nomura, Yusuke Yoshimatsu, Shun Tanemoto, Satoko Umeda, Keiko Ono, Yohei Mikami, Nobuhiro Nakamoto, Kaoru Takabayashi, Naoki Hosoe, Haruhiko Ogata, Tuneo Ikenoue, Atsushi Hirao, Yoshiaki Kubota, Takanori Kanai

Research output: Contribution to journalArticlepeer-review

Abstract

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, DPIELs) originated from CD4+CD8αTCRβ+ T cells (single positive, SPIELs) 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 DPIELs increased more than natural IELs in this location. Moreover, DPIELs consumed less oxygen and glucose and exhibited unique alterations in mitochondria. Using inhibitors and genetically modified mice, we revealed that DPIELs 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.

Original languageEnglish
Article number104021
JournaliScience
Volume25
Issue number4
DOIs
Publication statusPublished - 2022 Apr 15

Keywords

  • Biological sciences
  • Cell biology
  • Components of the immune system
  • Immunology

ASJC Scopus subject areas

  • General

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