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

Cell. 2018 Jul 12;174(2):285-299.e12. doi: 10.1016/j.cell.2018.05.004. Epub 2018 Jun 7.


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.

Keywords: Foxp3; IL-33; PPARγ; TCR transgenic mice; adipose tissue; immunometabolism; immunoregulation; regulatory T cell.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Chromatin Assembly and Disassembly
  • Forkhead Transcription Factors / metabolism
  • 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
  • PPAR gamma / genetics
  • PPAR gamma / metabolism
  • Phenotype
  • RNA / chemistry
  • RNA / isolation & purification
  • RNA / metabolism
  • Receptors, Antigen, T-Cell / genetics*
  • Receptors, Antigen, T-Cell / metabolism
  • Receptors, Interleukin / metabolism
  • Single-Cell Analysis
  • Spleen / immunology
  • Spleen / metabolism
  • T-Lymphocytes, Regulatory / cytology
  • T-Lymphocytes, Regulatory / immunology
  • T-Lymphocytes, Regulatory / metabolism*
  • Transcriptome


  • Forkhead Transcription Factors
  • Foxp3 protein, mouse
  • Il1rl1 protein, mouse
  • Interleukin-1 Receptor-Like 1 Protein
  • PPAR gamma
  • Receptors, Antigen, T-Cell
  • Receptors, Interleukin
  • RNA