Discovery of surrogate agonists for visceral fat Treg cells that modulate metabolic indices in vivo

• Published in: eLife Vol. 9
• Main Authors: Fernandes, Ricardo A, Li, Chaoran, Wang, Gang, Yang, Xinbo, Savvides, Christina S, Glassman, Caleb R, Dong, Shen, Luxenberg, Eric, Sibener, Leah V, Birnbaum, Michael E, Benoist, Christophe, Mathis, Diane, Garcia, K Christopher
• Format: Journal Article
• Language: English
• Published: England eLife Science Publications, Ltd 10.08.2020; eLife Sciences Publications Ltd; eLife Sciences Publications, Ltd
• Subjects: Adipose tissue; Agonists; Animals; Antigens; Cells (Biology); HEK293 Cells; Homeostasis; Humans; Immunization; Immunology and Inflammation; inflammation; Inflammation - metabolism; Insulin; Insulin Resistance - physiology; Intra-Abdominal Fat - metabolism; Jurkat Cells; K562 Cells; Ligands; Lymphocytes T; Major histocompatibility complex; Male; Metabolic disorders; Metabolism; Mice; Mice, Transgenic; Mutation; Peptide Library; Peptides; surrogate antigens; T cell receptors; T-Lymphocytes, Regulatory - physiology; Transcription; Treg cells; Tumor necrosis factor-α; adipose tissue; mouse; Treg cells; inflammation; surrogate antigens; immunology
• ISSN: 2050-084X; 2050-084X
• DOI: 10.7554/eLife.58463

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 A b -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 TNFα 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.