Costimulation via the tumor-necrosis factor receptor superfamily couples TCR signal strength to the thymic differentiation of regulatory T cells

Nat Immunol. 2014 May;15(5):473-81. doi: 10.1038/ni.2849. Epub 2014 Mar 16.

Abstract

Regulatory T cells (Treg cells) express members of the tumor-necrosis factor (TNF) receptor superfamily (TNFRSF), but the role of those receptors in the thymic development of Treg cells is undefined. We found here that Treg cell progenitors had high expression of the TNFRSF members GITR, OX40 and TNFR2. Expression of those receptors correlated directly with the signal strength of the T cell antigen receptor (TCR) and required the coreceptor CD28 and the kinase TAK1. The neutralization of ligands that are members of the TNF superfamily (TNFSF) diminished the development of Treg cells. Conversely, TNFRSF agonists enhanced the differentiation of Treg cell progenitors by augmenting responsiveness of the interleukin 2 receptor (IL-2R) and transcription factor STAT5. Costimulation with the ligand of GITR elicited dose-dependent enrichment for cells of lower TCR affinity in the Treg cell repertoire. In vivo, combined inhibition of GITR, OX40 and TNFR2 abrogated the development of Treg cells. Thus, expression of members of the TNFRSF on Treg cell progenitors translated strong TCR signals into molecular parameters that specifically promoted the development of Treg cells and shaped the Treg cell repertoire.

Publication types

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

MeSH terms

  • Animals
  • CD28 Antigens / genetics
  • CD28 Antigens / metabolism
  • Cell Differentiation / genetics
  • Cells, Cultured
  • Glucocorticoid-Induced TNFR-Related Protein / genetics
  • Glucocorticoid-Induced TNFR-Related Protein / metabolism
  • MAP Kinase Kinase Kinases / genetics
  • MAP Kinase Kinase Kinases / metabolism
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Receptor Cross-Talk* / immunology
  • Receptors, Antigen, T-Cell / agonists*
  • Receptors, OX40 / genetics
  • Receptors, OX40 / metabolism
  • Receptors, Tumor Necrosis Factor, Type II / metabolism
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / pharmacology
  • STAT5 Transcription Factor / metabolism
  • Signal Transduction / genetics
  • T-Lymphocytes, Regulatory / immunology*
  • Thymus Gland / immunology*
  • Tumor Necrosis Factor Receptor-Associated Peptides and Proteins / genetics
  • Tumor Necrosis Factor Receptor-Associated Peptides and Proteins / metabolism*

Substances

  • CD28 Antigens
  • Glucocorticoid-Induced TNFR-Related Protein
  • Receptors, Antigen, T-Cell
  • Receptors, OX40
  • Receptors, Tumor Necrosis Factor, Type II
  • Recombinant Fusion Proteins
  • STAT5 Transcription Factor
  • Tnfrsf18 protein, mouse
  • Tnfrsf4 protein, mouse
  • Tumor Necrosis Factor Receptor-Associated Peptides and Proteins
  • MAP Kinase Kinase Kinases
  • MAP kinase kinase kinase 7