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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 A\n                    <jats:sup>b<\/jats:sup>\n                    -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 TNF\u03b1 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.\n                  <\/jats:p>","DOI":"10.7554\/elife.58463","type":"journal-article","created":{"date-parts":[[2020,8,10]],"date-time":"2020-08-10T08:00:32Z","timestamp":1597046432000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.58463","source":"Crossref","is-referenced-by-count":28,"title":["Discovery of surrogate agonists for visceral fat Treg cells that modulate metabolic indices in vivo"],"prefix":"10.7554","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5343-3334","authenticated-orcid":true,"given":"Ricardo A","family":"Fernandes","sequence":"first","affiliation":[{"name":"Departments of Molecular and Cellular Physiology and Structural Biology, Stanford University School of Medicine, Stanford, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chaoran","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Immunology, Harvard Medical School; and Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women\u2019s Hospital, Boston, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gang","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Immunology, Harvard Medical School; and Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women\u2019s Hospital, Boston, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinbo","family":"Yang","sequence":"additional","affiliation":[{"name":"Departments of Molecular and Cellular Physiology and Structural Biology, Stanford University School of Medicine, Stanford, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christina S","family":"Savvides","sequence":"additional","affiliation":[{"name":"Departments of Molecular and Cellular Physiology and Structural Biology, Stanford University School of Medicine, Stanford, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caleb R","family":"Glassman","sequence":"additional","affiliation":[{"name":"Departments of Molecular and Cellular Physiology and Structural Biology, Stanford University School of Medicine, Stanford, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shen","family":"Dong","sequence":"additional","affiliation":[{"name":"Departments of Molecular and Cellular Physiology and Structural Biology, Stanford University School of Medicine, Stanford, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric","family":"Luxenberg","sequence":"additional","affiliation":[{"name":"Department of Electrical Engineering, Stanford University School of Engineering, Stanford, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leah V","family":"Sibener","sequence":"additional","affiliation":[{"name":"Departments of Molecular and Cellular Physiology and Structural Biology, Stanford University School of Medicine, Stanford, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael E","family":"Birnbaum","sequence":"additional","affiliation":[{"name":"Departments of Molecular and Cellular Physiology and Structural Biology, Stanford University School of Medicine, Stanford, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christophe","family":"Benoist","sequence":"additional","affiliation":[{"name":"Department of Immunology, Harvard Medical School; 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