The adaptor TRAF3 restrains the lineage determination of thymic regulatory T cells by modulating signaling via the receptor for IL-2

Nat Immunol. 2014 Sep;15(9):866-74. doi: 10.1038/ni.2944. Epub 2014 Jul 20.

Abstract

The number of Foxp3+ regulatory T cells (Treg cells) must be tightly controlled for efficient suppression of autoimmunity with no impairment of normal immune responses. Here we found that the adaptor TRAF3 was intrinsically required for restraining the lineage determination of thymic Treg cells. T cell-specific deficiency in TRAF3 resulted in a two- to threefold greater frequency of Treg cells, due to the more efficient transition of precursors of Treg cells into Foxp3+ Treg cells. TRAF3 dampened interleukin 2 (IL-2) signaling by facilitating recruitment of the tyrosine phosphatase TCPTP to the IL-2 receptor complex, which resulted in dephosphorylation of the signaling molecules Jak1 and Jak3 and negative regulation of signaling via Jak and the transcription factor STAT5. Our results identify a role for TRAF3 as an important negative regulator of signaling via the IL-2 receptor that affects the development of Treg cells.

Publication types

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

MeSH terms

  • Animals
  • Autoimmunity / immunology
  • Cell Differentiation / immunology*
  • Forkhead Transcription Factors / immunology
  • Interleukin-2 / immunology*
  • Janus Kinase 1 / immunology
  • Janus Kinase 3 / immunology
  • Mice
  • Protein Tyrosine Phosphatase, Non-Receptor Type 2 / immunology
  • STAT5 Transcription Factor / immunology
  • Signal Transduction / immunology*
  • T-Lymphocytes, Regulatory / immunology*
  • TNF Receptor-Associated Factor 3 / immunology*
  • Thymus Gland / cytology*

Substances

  • Forkhead Transcription Factors
  • Foxp3 protein, mouse
  • Interleukin-2
  • STAT5 Transcription Factor
  • TNF Receptor-Associated Factor 3
  • Janus Kinase 1
  • Janus Kinase 3
  • Protein Tyrosine Phosphatase, Non-Receptor Type 2