Abstract B065: Tracking adipose-tissue Treg provenance, dependencies, and activities via T-cell receptor transgenic mice

Abstract

Abstract Recent epidemiologic and animal model studies indicate that overweight and obese individuals have increased risk of type-2 diabetes, cardiovascular diseases and certain types of cancer. It was suggested that chronic, low-grade inflammation of the adipose tissue, and eventually systemically, is one of the major causes for obesity-associated metabolic abnormalities and cancer. Regulatory T (Treg) cells located within parenchymal tissues safeguard tissue homeostasis and suppress inflammation. A paradigmatic “tissue-Treg” population is that found in visceral- adipose tissue (VAT) of male mice. VAT-Treg cells have a unique transcriptome, are clonally expanded, and promote metabolic health through effects on local immunocytes and adipocytes. Because of their rarity and inaccessibility, cardinal questions such as what factors control their accumulation in fat and when/where/how do they adopt their distinctive phenotype remained unanswered. We addressed these issues using VAT- Treg T-cell-receptor (TCR) transgenic mice and reporter mice for the diagnostic VAT-Treg transcription factor, PPARγ. Accumulation of VAT-Tregs was driven by combined effects of TCR specificity, Foxp3 expression, and a cell-intrinsic response to interleukin-33. Their characteristic phenotype emerged in two stages: a minority of splenic Treg cells weakly up-regulated a slice of the VAT-Treg transcriptional signature, reflecting cell activation, but the definitive phenotype, arming cells for fat survival, was manifest only in VAT. This deeper understanding of tissue-Treg generation should facilitate precision-targeting strategies. Citation Format: Chaoran Li, Joanna R. DiSpirito, David Zemmour, Raul German Spallanzani, Wilson Kuswanto, Christophe Benoist, Diane Mathis. Tracking adipose-tissue Treg provenance, dependencies, and activities via T-cell receptor transgenic mice [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr B065.