TGF-β cytokine signaling promotes CD8+ T cell development and low-affinity CD4+ T cell homeostasis by regulation of interleukin-7 receptor α expression

Immunity. 2013 Aug 22;39(2):335-46. doi: 10.1016/j.immuni.2013.07.016. Epub 2013 Aug 8.

Abstract

Interleukin-7 receptor α chain (IL-7Rα) is induced upon T cell positive selection and controls thymic CD8-lineage specification and peripheral naive T cell homeostasis. How IL-7Rα expression is regulated in developing thymocytes is unclear. Here, we show that transforming growth factor β (TGF-β) signaling promoted IL-7Rα expression and CD8+ T cell differentiation. In addition, TGF-β signaling was required for high IL-7Rα expression in CD4+ T cells bearing low-affinity T cell receptors, and the abrogation of TGF-β receptor expression led to failed maintenance of peripheral CD4+ T cells. Compromised IL-7Rα expression in TGF-β-receptor-deficient T cells was associated with increased expression of the Il7ra transcriptional repressor, Gfi-1. IL-7Rα transgenesis or T-cell-specific ablation of Gfi-1 restored IL-7Rα expression and largely ameliorated the development and homeostasis defects of TGF-β-receptor-deficient T cells. These findings reveal functions for TGF-β signaling in controlling IL-7Rα expression and in promoting T cell repertoire diversification.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural

MeSH terms

  • Animals
  • CD4-Positive T-Lymphocytes / immunology*
  • CD8-Positive T-Lymphocytes / immunology
  • CD8-Positive T-Lymphocytes / metabolism*
  • Cell Differentiation
  • Cell Lineage
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Homeostasis
  • Mice
  • Mice, Knockout
  • Protein Serine-Threonine Kinases / deficiency
  • Protein Serine-Threonine Kinases / genetics
  • Protein Serine-Threonine Kinases / metabolism
  • Receptor, Transforming Growth Factor-beta Type II
  • Receptors, Antigen, T-Cell
  • Receptors, Interleukin-7 / immunology
  • Receptors, Interleukin-7 / metabolism*
  • Receptors, Transforming Growth Factor beta / deficiency
  • Receptors, Transforming Growth Factor beta / genetics
  • Receptors, Transforming Growth Factor beta / metabolism
  • Signal Transduction
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Transforming Growth Factor beta / metabolism*

Substances

  • DNA-Binding Proteins
  • Gfi1 protein, mouse
  • Receptors, Antigen, T-Cell
  • Receptors, Interleukin-7
  • Receptors, Transforming Growth Factor beta
  • Transcription Factors
  • Transforming Growth Factor beta
  • interleukin-7 receptor, alpha chain
  • Protein Serine-Threonine Kinases
  • Receptor, Transforming Growth Factor-beta Type II