Tissue environment, not ontogeny, defines murine intestinal intraepithelial T lymphocytes
- University of Dundee, United Kingdom
Abstract
Tissue-resident intestinal intraepithelial T lymphocytes (T-IEL) patrol the gut and have important roles in regulating intestinal homeostasis. T-IEL include both induced T-IEL, derived from systemic antigen-experienced lymphocytes, and natural IEL, which are developmentally targeted to the intestine. While the processes driving T-IEL development have been elucidated, the precise roles of the different subsets and the processes driving activation and regulation of these cells remain unclear. To gain functional insights into these enigmatic cells, we used high-resolution, quantitative mass spectrometry to compare the proteomes of induced T-IEL and natural T-IEL subsets, with naive CD8+ T cells from lymph nodes. This data exposes the dominant effect of the gut environment over ontogeny on T-IEL phenotypes. Analyses of protein copy numbers of >7000 proteins in T-IEL reveal skewing of the cell surface repertoire towards epithelial interactions and checkpoint receptors; strong suppression of the metabolic machinery indicating a high energy barrier to functional activation; upregulated cholesterol and lipid metabolic pathways, leading to high cholesterol levels in T-IEL; suppression of T cell antigen receptor signalling and expression of the transcription factor TOX, reminiscent of chronically activated T cells. These novel findings illustrate how T-IEL integrate multiple tissue-specific signals to maintain their homeostasis and potentially function.
Data availability
The raw and processed mass spectrometry proteomics data have been deposited to the ProteomeXchange Consortium via the PRIDE partner repository (Perez-Riverol et al., 2019) with the dataset identifier PXD023140 (https://www.ebi.ac.uk/pride/archive/projects/PXD023140/). All other data generated in this study are included within the manuscript and supporting files.
Article and author information
Author details
Alejandro J Brenes
Funding
Wellcome Trust (105024/Z/14/Z)
- Angus I Lamond
Wellcome Trust (206246/Z/17/Z)
- Mahima Swamy
Wellcome Trust (215309/Z/19/Z)
- Olivia J James
Wellcome Trust (222320/Z/21/Z)
- Harriet Watt
Wellcome Trust (073980/Z/03/Z)
- Angus I Lamond
Wellcome Trust (098503/E/12/Z)
- Angus I Lamond
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Carla V Rothlin, Yale School of Medicine, United States
Ethics
Animal experimentation: All mice were bred and maintained with approval by the University of Dundee ethical review committee in compliance with U.K. Home Office Animals (Scientific Procedures) Act 1986 guidelines. C57BL/6J mice were purchased from Charles Rivers and acclimatised for a minimum of 10 days prior to use in experiments. Mice were maintained in a standard barrier facility on a 12hour light/dark cycle at 21oC, 45-65% relative humidity, in individually ventilated cages with corn cob and sizzler-nest material and fed an R&M3 diet (Special Diet Services, UK) and filtered water ad libitum. Cages were changed at least every two weeks. For all experiments, mice were used between 8-12 weeks of age, and for proteomics, male mice aged 8-9 weeks were used.
Version history
- Preprint posted: March 16, 2021 (view preprint)
- Received: May 11, 2021
- Accepted: September 1, 2021
- Accepted Manuscript published: September 2, 2021 (version 1)
- Accepted Manuscript updated: September 3, 2021 (version 2)
- Accepted Manuscript updated: September 8, 2021 (version 3)
- Version of Record published: September 24, 2021 (version 4)
Copyright
© 2021, Brenes et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Tissue environment, not ontogeny, defines murine intestinal intraepithelial T lymphocytes
eLife 10:e70055.
https://doi.org/10.7554/eLife.70055
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