TCR Transgenic Mice Reveal Stepwise, Multi-site Acquisition of the Distinctive Fat-Treg Phenotype

• Published in: Cell Vol. 174; no. 2; pp. 285 - 299.e12
• Main Authors: Li, Chaoran, DiSpirito, Joanna R., Zemmour, David, Spallanzani, Raul German, Kuswanto, Wilson, Benoist, Christophe, Mathis, Diane
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 12.07.2018
• Subjects: adipose tissue; Animals; Chromatin Assembly and Disassembly; Forkhead Transcription Factors - metabolism; Foxp3; IL-33; immunometabolism; immunoregulation; Interleukin-1 Receptor-Like 1 Protein - genetics; Interleukin-1 Receptor-Like 1 Protein - metabolism; Intra-Abdominal Fat - immunology; Intra-Abdominal Fat - metabolism; Macrophages - cytology; Macrophages - immunology; Macrophages - metabolism; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Phenotype; PPAR gamma - genetics; PPAR gamma - metabolism; PPARγ; Receptors, Antigen, T-Cell - genetics; Receptors, Antigen, T-Cell - metabolism; Receptors, Interleukin - metabolism; regulatory T cell; RNA - chemistry; RNA - isolation & purification; RNA - metabolism; Single-Cell Analysis; Spleen - immunology; Spleen - metabolism; T-Lymphocytes, Regulatory - cytology; T-Lymphocytes, Regulatory - immunology; T-Lymphocytes, Regulatory - metabolism; TCR transgenic mice; Transcriptome; immunometabolism; adipose tissue; immunoregulation; Foxp3; TCR transgenic mice; IL-33; PPARγ; regulatory T cell
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/j.cell.2018.05.004

Visceral adipose tissue (VAT) hosts a population of regulatory T (Treg) cells, with a unique phenotype, that controls local and systemic inflammation and metabolism. Generation of a T cell receptor transgenic mouse line, wherein VAT Tregs are highly enriched, facilitated study of their provenance, dependencies, and activities. We definitively established a role for T cell receptor specificity, uncovered an unexpected function for the primordial Treg transcription-factor, Foxp3, evidenced a cell-intrinsic role for interleukin-33 receptor, and ordered these dependencies within a coherent scenario. Genesis of the VAT-Treg phenotype entailed a priming step in the spleen, permitting them to exit the lymphoid organs and surveil nonlymphoid tissues, and a final diversification process within VAT, in response to microenvironmental cues. Understanding the principles of tissue-Treg biology is a prerequisite for precision-targeting strategies. [Display omitted] •VAT-Treg TCR-transgenic mice recapitulate the major aspects of VAT-Treg biology•VAT-Treg accumulation depends on the TCR, Foxp3, and the IL-33 receptor•The VAT-Treg phenotype is set via a two-step, lymphoid:nonlymphoid scenario•Substantial epigenetic remodeling accompanies final diversification of Tregs in VAT The accumulation of regulatory T cells in visceral adipose tissue is the result of molecular and microenvironmental cues that drive cellular activation in the spleen, egress from lymphoid tissues, and final diversification in adipose tissue.