Intracellular Metabolic Adaptation of Intraepithelial CD4CD8αα T Lymphocytes

Overview

Journal iScience

Publisher Cell Press

Date 2022 Mar 22

PMID 35313689

Authors

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

Affiliations

Soon will be listed here.

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 CD4CD8ααTCRβ T cells (double positive, DP) originated from CD4CD8αTCRβ T cells (single positive, SP) 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 increased more than natural IELs in this location. Moreover, DP consumed less oxygen and glucose and exhibited unique alterations in mitochondria. Using inhibitors and genetically modified mice, we revealed that DP 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.

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References

Almeida L, Lochner M, Berod L, Sparwasser T . Metabolic pathways in T cell activation and lineage differentiation. Semin Immunol. 2016; 28(5):514-524. DOI: 10.1016/j.smim.2016.10.009. View

Konjar S, Frising U, Ferreira C, Hinterleitner R, Mayassi T, Zhang Q . Mitochondria maintain controlled activation state of epithelial-resident T lymphocytes. Sci Immunol. 2018; 3(24). PMC: 6690060. DOI: 10.1126/sciimmunol.aan2543. View

Raud B, McGuire P, Jones R, Sparwasser T, Berod L . Fatty acid metabolism in CD8 T cell memory: Challenging current concepts. Immunol Rev. 2018; 283(1):213-231. PMC: 6691976. DOI: 10.1111/imr.12655. View

Jung J, Zeng H, Horng T . Metabolism as a guiding force for immunity. Nat Cell Biol. 2019; 21(1):85-93. DOI: 10.1038/s41556-018-0217-x. View

Cheroutre H, Lambolez F, Mucida D . The light and dark sides of intestinal intraepithelial lymphocytes. Nat Rev Immunol. 2011; 11(7):445-56. PMC: 3140792. DOI: 10.1038/nri3007. View

Buck M, OSullivan D, Geltink R, Curtis J, Chang C, Sanin D . Mitochondrial Dynamics Controls T Cell Fate through Metabolic Programming. Cell. 2016; 166(1):63-76. PMC: 4974356. DOI: 10.1016/j.cell.2016.05.035. View

Neff F, Flores-Dominguez D, Ryan D, Horsch M, Schroder S, Adler T . Rapamycin extends murine lifespan but has limited effects on aging. J Clin Invest. 2013; 123(8):3272-91. PMC: 3726163. DOI: 10.1172/JCI67674. View

Hoytema van Konijnenburg D, Reis B, Pedicord V, Farache J, Victora G, Mucida D . Intestinal Epithelial and Intraepithelial T Cell Crosstalk Mediates a Dynamic Response to Infection. Cell. 2017; 171(4):783-794.e13. PMC: 5670000. DOI: 10.1016/j.cell.2017.08.046. View

Dodd K, Yang J, Shen M, Sampson J, Tee A . mTORC1 drives HIF-1α and VEGF-A signalling via multiple mechanisms involving 4E-BP1, S6K1 and STAT3. Oncogene. 2014; 34(17):2239-50. PMC: 4172452. DOI: 10.1038/onc.2014.164. View

10.

Bilate A, Bousbaine D, Mesin L, Agudelo M, Leube J, Kratzert A . Tissue-specific emergence of regulatory and intraepithelial T cells from a clonal T cell precursor. Sci Immunol. 2017; 1(2):eaaf7471. PMC: 6296461. DOI: 10.1126/sciimmunol.aaf7471. View

11.

Pan Y, Tian T, Park C, Lofftus S, Mei S, Liu X . Survival of tissue-resident memory T cells requires exogenous lipid uptake and metabolism. Nature. 2017; 543(7644):252-256. PMC: 5509051. DOI: 10.1038/nature21379. View

12.

RYAN H, Poloni M, McNULTY W, Elson D, Gassmann M, Arbeit J . Hypoxia-inducible factor-1alpha is a positive factor in solid tumor growth. Cancer Res. 2000; 60(15):4010-5. View

13.

Vandereyken M, James O, Swamy M . Mechanisms of activation of innate-like intraepithelial T lymphocytes. Mucosal Immunol. 2020; 13(5):721-731. PMC: 7434593. DOI: 10.1038/s41385-020-0294-6. View

14.

Van Kaer L, Olivares-Villagomez D . Development, Homeostasis, and Functions of Intestinal Intraepithelial Lymphocytes. J Immunol. 2018; 200(7):2235-2244. PMC: 5863587. DOI: 10.4049/jimmunol.1701704. View

15.

Fahrer A, Konigshofer Y, Kerr E, Ghandour G, Mack D, Davis M . Attributes of gammadelta intraepithelial lymphocytes as suggested by their transcriptional profile. Proc Natl Acad Sci U S A. 2001; 98(18):10261-6. PMC: 56949. DOI: 10.1073/pnas.171320798. View

16.

Phan A, Doedens A, Palazon A, Tyrakis P, Cheung K, Johnson R . Constitutive Glycolytic Metabolism Supports CD8 T Cell Effector Memory Differentiation during Viral Infection. Immunity. 2016; 45(5):1024-1037. PMC: 5130099. DOI: 10.1016/j.immuni.2016.10.017. View

17.

Magee J, Ikenoue T, Nakada D, Lee J, Guan K, Morrison S . Temporal changes in PTEN and mTORC2 regulation of hematopoietic stem cell self-renewal and leukemia suppression. Cell Stem Cell. 2012; 11(3):415-28. PMC: 3447536. DOI: 10.1016/j.stem.2012.05.026. View

18.

Gruber M, Hu C, Johnson R, Brown E, Keith B, Simon M . Acute postnatal ablation of Hif-2alpha results in anemia. Proc Natl Acad Sci U S A. 2007; 104(7):2301-6. PMC: 1892942. DOI: 10.1073/pnas.0608382104. View

19.

Sujino T, London M, Hoytema van Konijnenburg D, Rendon T, Buch T, Silva H . Tissue adaptation of regulatory and intraepithelial CD4⁺ T cells controls gut inflammation. Science. 2016; 352(6293):1581-6. PMC: 4968079. DOI: 10.1126/science.aaf3892. View

20.

Pearce E, Pearce E . Metabolic pathways in immune cell activation and quiescence. Immunity. 2013; 38(4):633-43. PMC: 3654249. DOI: 10.1016/j.immuni.2013.04.005. View