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.
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.
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.
Metrics
-
- 2,909
- views
-
- 369
- downloads
-
- 18
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Tissue environment, not ontogeny, defines murine intestinal intraepithelial T lymphocytes
eLife 10:e70055.
https://doi.org/10.7554/eLife.70055
Further reading
-
- Genetics and Genomics
- Immunology and Inflammation
Systemic lupus erythematosus (SLE) is an autoimmune disease, the pathophysiology and genetic basis of which are incompletely understood. Using a forward genetic screen in multiplex families with SLE, we identified an association between SLE and compound heterozygous deleterious variants in the non-receptor tyrosine kinases (NRTKs) ACK1 and BRK. Experimental blockade of ACK1 or BRK increased circulating autoantibodies in vivo in mice and exacerbated glomerular IgG deposits in an SLE mouse model. Mechanistically, NRTKs regulate activation, migration, and proliferation of immune cells. We found that the patients’ ACK1 and BRK variants impair efferocytosis, the MERTK-mediated anti-inflammatory response to apoptotic cells, in human induced pluripotent stem cell (hiPSC)-derived macrophages, which may contribute to SLE pathogenesis. Overall, our data suggest that ACK1 and BRK deficiencies are associated with human SLE and impair efferocytosis in macrophages.
-
- Immunology and Inflammation
The adaptive T cell response is accompanied by continuous rewiring of the T cell’s electric and metabolic state. Ion channels and nutrient transporters integrate bioelectric and biochemical signals from the environment, setting cellular electric and metabolic states. Divergent electric and metabolic states contribute to T cell immunity or tolerance. Here, we report in mice that neuritin (Nrn1) contributes to tolerance development by modulating regulatory and effector T cell function. Nrn1 expression in regulatory T cells promotes its expansion and suppression function, while expression in the T effector cell dampens its inflammatory response. Nrn1 deficiency in mice causes dysregulation of ion channel and nutrient transporter expression in Treg and effector T cells, resulting in divergent metabolic outcomes and impacting autoimmune disease progression and recovery. These findings identify a novel immune function of the neurotrophic factor Nrn1 in regulating the T cell metabolic state in a cell context-dependent manner and modulating the outcome of an immune response.
