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

doi:10.1016/j.isci.2022.104021

Intracellular metabolic adaptation of intraepithelial CD4⁺CD8αα⁺ T lymphocytes

iScience. 2022 Mar 4;25(4):104021. doi: 10.1016/j.isci.2022.104021. eCollection 2022 Apr 15.

Authors

Yosuke Harada¹, Tomohisa Sujino², Kentaro Miyamoto^{1

3}, Ena Nomura¹, Yusuke Yoshimatsu¹, Shun Tanemoto¹, Satoko Umeda¹, Keiko Ono¹, Yohei Mikami¹, Nobuhiro Nakamoto¹, Kaoru Takabayashi², Naoki Hosoe², Haruhiko Ogata², Tuneo Ikenoue⁴, Atsushi Hirao⁵, Yoshiaki Kubota⁶, Takanori Kanai¹

Affiliations

¹ Department of Gastroenterology, Keio University School of Medicine, 35, Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.
² Center for Diagnostic and Therapeutic Endoscopy, Keio University Hospital, 35, Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.
³ Miyarisan Pharmaceutical Co. Ltd. Tokyo 114-0016, Japan.
⁴ Division of Clinical Genome Research, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
⁵ Division of Molecular Genetics, Cancer Research Institute, Kanazawa University, Kanazawa, Japan.
⁶ Department of Anatomy, Keio University School of Medicine, Tokyo 160-8582, Japan.

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, 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.

Keywords: Biological sciences; Cell biology; Components of the immune system; Immunology.