A Two-Step Process for Thymic Regulatory T Cell Development

Immunity. 2008 Jan;28(1):100-11. doi: 10.1016/j.immuni.2007.11.021.

Abstract

Recognition of self-antigens is required for regulatory T (Treg) cells to exert dominant tolerance. However, the mechanism by which self-reactive thymocytes are diverted into the Treg cell subset is unclear. To address this question, we looked for the immediate precursors to Treg cells within Foxp3(-)CD4+CD8(-) thymocytes. By using intrathymic transfer, we found that the CD25hi subset is highly enriched in Treg cell precursors. This was supported by tracking of thymocyte development via analysis of T cell receptor (TCR) repertoires in a TCR-beta transgenic model. These Treg cell precursors exist at a developmental stage where they are poised to express Foxp3 without further TCR engagement, requiring only stimulation by interleukin-2 (IL-2) or IL-15. Thus, we propose that the selection of self-reactive thymocytes into the Treg cell subset occurs via an instructive rather than stochastic-selective model whereby TCR signals result in the expression of proximal IL-2 signaling components facilitating cytokine-mediated induction of Foxp3.

Publication types

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

MeSH terms

  • Animals
  • Cell Differentiation / immunology*
  • Flow Cytometry
  • Forkhead Transcription Factors / immunology
  • Forkhead Transcription Factors / metabolism
  • Interleukin-2 / immunology
  • Interleukin-2 / metabolism
  • Interleukin-2 Receptor alpha Subunit / immunology
  • Interleukin-2 Receptor alpha Subunit / metabolism
  • Lymphocyte Activation / immunology
  • Mice
  • Mice, Transgenic
  • Receptors, Antigen, T-Cell / immunology
  • Receptors, Antigen, T-Cell / metabolism
  • STAT5 Transcription Factor / immunology
  • STAT5 Transcription Factor / metabolism
  • Self Tolerance / immunology*
  • Stem Cells / cytology
  • Stem Cells / immunology
  • Stem Cells / metabolism
  • T-Lymphocyte Subsets / cytology*
  • T-Lymphocyte Subsets / immunology
  • T-Lymphocytes, Regulatory / cytology*
  • T-Lymphocytes, Regulatory / immunology
  • Thymus Gland / cytology*
  • Thymus Gland / immunology

Substances

  • Forkhead Transcription Factors
  • Foxp3 protein, mouse
  • Interleukin-2
  • Interleukin-2 Receptor alpha Subunit
  • Receptors, Antigen, T-Cell
  • STAT5 Transcription Factor