Linked T cell receptor and cytokine signaling govern the development of the regulatory T cell repertoire

Immunity. 2008 Jan;28(1):112-21. doi: 10.1016/j.immuni.2007.11.022.


Appropriate development of regulatory T (Treg) cells is necessary to prevent autoimmunity. Neonatal mice, unlike adults, lack factors required for Treg cell development. It is unclear what these missing factors are. However, signals emanating from the T cell receptor (TCR), the costimulatory receptor CD28, and the family of gammac-dependent cytokine receptors are required for Treg cell development. Herein we demonstrate that expression of a constitutively active Stat5b transgene (Stat5b-CA) allowed for Treg cell development in neonatal mice and restored Treg cell numbers in Cd28(-/-) mice. Sequence analysis of TCR genes in Stat5b-CA Treg cells indicated that ectopic STAT5 activation resulted in a TCR repertoire that more closely resembled that of naive T cells. Using MHCII tetramers to identify antigen-specific T cells, we showed that STAT5 signals diverted thymocytes normally destined to become naive T cells into the Treg cell lineage. Our data support a two-step model of Treg cell differentiation in which TCR and CD28 signals induce cytokine responsiveness and STAT5-inducing cytokines then complete the program of Treg cell differentiation.

Publication types

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

MeSH terms

  • Animals
  • Animals, Newborn
  • Blotting, Western
  • CD28 Antigens / immunology
  • CD28 Antigens / metabolism
  • Cell Differentiation / immunology*
  • Cell Lineage / immunology
  • Cytokines / biosynthesis*
  • Flow Cytometry
  • Forkhead Transcription Factors / immunology
  • Forkhead Transcription Factors / metabolism
  • Mice
  • Mice, Transgenic
  • Receptors, Antigen, T-Cell / genetics
  • Receptors, Antigen, T-Cell / immunology*
  • STAT5 Transcription Factor / immunology
  • STAT5 Transcription Factor / metabolism
  • Self Tolerance / immunology*
  • Sequence Analysis
  • Signal Transduction / immunology*
  • T-Lymphocytes, Regulatory / cytology*


  • CD28 Antigens
  • Cytokines
  • Forkhead Transcription Factors
  • Foxp3 protein, mouse
  • Receptors, Antigen, T-Cell
  • STAT5 Transcription Factor
  • Stat5b protein, mouse