Discovery of surrogate agonists for visceral fat Treg cells that modulate metabolic indices in vivo
- Stanford University School of Medicine, United States
- Harvard Medical School, United States
- Stanford University School of Engineering, United States
- Howard Hughes Medical Institute, Stanford University School of Medicine, United States
Abstract
T regulatory (Treg) cells play vital roles in modulating immunity and tissue homeostasis. Their actions depend on TCR recognition of peptide-MHC molecules; yet the degree of peptide specificity of Treg-cell function, and whether Treg ligands can be used to manipulate Treg cell biology are unknown. Here, we developed an Ab-peptide library that enabled unbiased screening of peptides recognized by a bona fide murine Treg cell clone isolated from the visceral adipose tissue (VAT), and identified surrogate agonist peptides, with differing affinities and signaling potencies. The VAT-Treg cells expanded in vivo by one of the surrogate agonists preserved the typical VAT-Treg transcriptional programs. Immunization with this surrogate, especially when coupled with blockade of TNFa signaling, expanded VAT-Treg cells, resulting in protection from inflammation and improved metabolic indices, including promotion of insulin sensitivity. These studies suggest that antigen-specific targeting of VAT-localized Treg cells could eventually be a strategy for improving metabolic disease.
Data availability
Sequencing data for the peptide-Ab yeast library screening and RNA-seq data for VAT-Treg cells have been deposited in GEO under accession codes GSE151070 and GSE150173. Custom Perl scripts for the processing of the deep sequencing data for the peptide-Ab is available from: https://github.com/jlmendozabio/NGSpeptideprepandpred.
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DNA sequencing for multiple rounds of the pMHC-yeast display selection for 2W, Yae and Fat TCRNCBI Gene Expression Omnibus, GSE151070.
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Transcriptional profiling of vTreg53 TCR transgenic Regulatory T (Treg) cells stimulated by agonist peptideNCBI Gene Expression Omnibus, GSE150173.
Article and author information
Author details
K Christopher Garcia
Funding
Wellcome (WT101609MA)
- Ricardo A Fernandes
NIH Office of the Director (5R01AI103867)
- K Christopher Garcia
Howard Hughes Medical Institute (HHMI)
- K Christopher Garcia
G Harold and Leila Y. Mathers Foundation
- K Christopher Garcia
NIH Clinical Center (2R01 DK092541)
- Diane Mathis
JPB Foundation
- Diane Mathis
NIH Office of the Director (UC4DK116264)
- K Christopher Garcia
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health and every effort was made to minimize suffering. All experiments were performed following animal protocols approved by the HMS Institutional Animal Use and Care Committee (protocol IS00001257).
Copyright
© 2020, Fernandes 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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Discovery of surrogate agonists for visceral fat Treg cells that modulate metabolic indices in vivo
eLife 9:e58463.
https://doi.org/10.7554/eLife.58463
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