A self-reactive TCR drives the development of Foxp3+ regulatory T cells that prevent autoimmune disease

J Immunol. 2011 Jul 15;187(2):861-9. doi: 10.4049/jimmunol.1004009. Epub 2011 Jun 20.

Abstract

Although Foxp3(+) regulatory T cells (Tregs) are thought to express autoreactive TCRs, it is not clear how individual TCRs influence Treg development, phenotype, and function in vivo. We have generated TCR transgenic mice (termed SFZ70 mice) using Tcra and Tcrb genes cloned from an autoreactive CD4(+) T cell isolated from a Treg-deficient scurfy mouse. The SFZ70 TCR recognizes a cutaneous autoantigen and drives development of both conventional CD4(+) Foxp3(-) T cells (T(conv)) and Foxp3(+) Tregs. SFZ70 Tregs display an activated phenotype evidenced by robust proliferation and expression of skin-homing molecules such as CD103 and P-selectin ligand. Analysis of Foxp3-deficient SFZ70 mice demonstrates that Tregs inhibit T(conv) cell expression of tissue-homing receptors and their production of proinflammatory cytokines. In addition, Treg suppression of SFZ70 T(conv) cells can be overcome by nonspecific activation of APCs. These results provide new insights into the differentiation and function of tissue-specific Tregs in vivo and provide a tractable system for analyzing the molecular requirements of Treg-mediated tolerance toward a cutaneous autoantigen.

Publication types

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

MeSH terms

  • Animals
  • Autoantigens / genetics
  • Autoantigens / metabolism*
  • Autoimmune Diseases / genetics
  • Autoimmune Diseases / pathology
  • Autoimmune Diseases / prevention & control*
  • Cell Differentiation / genetics
  • Cell Differentiation / immunology*
  • Cells, Cultured
  • Coculture Techniques
  • Epitopes, T-Lymphocyte / genetics
  • Epitopes, T-Lymphocyte / immunology
  • Forkhead Transcription Factors / biosynthesis*
  • Forkhead Transcription Factors / genetics
  • Immune Tolerance / genetics*
  • Lymphocyte Activation / genetics
  • Lymphocyte Activation / immunology
  • Lymphopenia / genetics
  • Lymphopenia / immunology
  • Lymphopenia / prevention & control
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Receptors, Antigen, T-Cell, alpha-beta / genetics
  • Receptors, Antigen, T-Cell, alpha-beta / metabolism*
  • Receptors, Antigen, T-Cell, alpha-beta / physiology
  • Skin / immunology
  • Skin / metabolism
  • Skin / pathology
  • T-Lymphocytes, Regulatory / immunology*
  • T-Lymphocytes, Regulatory / metabolism
  • T-Lymphocytes, Regulatory / pathology*
  • Thymus Gland / immunology
  • Thymus Gland / metabolism
  • Thymus Gland / pathology
  • Transcription, Genetic / immunology

Substances

  • Autoantigens
  • Epitopes, T-Lymphocyte
  • Forkhead Transcription Factors
  • Foxp3 protein, mouse
  • Receptors, Antigen, T-Cell, alpha-beta