Rapid and Efficient Generation of Regulatory T Cells to Commensal Antigens in the Periphery

Cell Rep. 2016 Sep 27;17(1):206-220. doi: 10.1016/j.celrep.2016.08.092.


Commensal bacteria shape the colonic regulatory T (Treg) cell population required for intestinal tolerance. However, little is known about this process. Here, we use the transfer of naive commensal-reactive transgenic T cells expressing colonic Treg T cell receptors (TCRs) to study peripheral Treg (pTreg) cell development in normal hosts. We found that T cells were activated primarily in the distal mesenteric lymph node. Treg cell induction was rapid, generating >40% Foxp3(+) cells 1 week after transfer. Contrary to prior reports, Foxp3(+) cells underwent the most cell divisions, demonstrating that pTreg cell generation can be the dominant outcome from naive T cell activation. Moreover, Notch2-dependent, but not Batf3-dependent, dendritic cells were involved in Treg cell selection. Finally, neither deletion of the conserved nucleotide sequence 1 (CNS1) region in Foxp3 nor blockade of TGF-β (transforming growth factor-β)-receptor signaling completely abrogated Foxp3 induction. Thus, these data show that pTreg cell selection to commensal bacteria is rapid, is robust, and may be specified by TGF-β-independent signals.

Keywords: CNS1 Foxp3; Notch2-dependent dendritic cells; TGFβ; commensal microbiota; pTreg; peripheral regulatory T cells.

Publication types

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

MeSH terms

  • Adoptive Transfer
  • Animals
  • Antigens, Bacterial / genetics
  • Antigens, Bacterial / immunology
  • Colon / immunology
  • Colon / microbiology
  • Dendritic Cells / cytology
  • Dendritic Cells / immunology*
  • Dendritic Cells / microbiology
  • Forkhead Transcription Factors / genetics
  • Forkhead Transcription Factors / immunology
  • Gastrointestinal Microbiome / immunology*
  • Gene Expression
  • Immune Tolerance*
  • Immunophenotyping
  • Lymph Nodes / immunology
  • Mesentery / immunology
  • Mice
  • Mice, Transgenic
  • Receptor, Notch2 / genetics
  • Receptor, Notch2 / immunology
  • Symbiosis / immunology*
  • T-Lymphocytes, Cytotoxic / cytology
  • T-Lymphocytes, Cytotoxic / immunology*
  • T-Lymphocytes, Cytotoxic / microbiology
  • T-Lymphocytes, Regulatory / cytology
  • T-Lymphocytes, Regulatory / immunology*
  • T-Lymphocytes, Regulatory / microbiology
  • Transforming Growth Factor beta / genetics
  • Transforming Growth Factor beta / immunology


  • Antigens, Bacterial
  • Forkhead Transcription Factors
  • Foxp3 protein, mouse
  • Notch2 protein, mouse
  • Receptor, Notch2
  • Transforming Growth Factor beta