CARMA1 controls an early checkpoint in the thymic development of FoxP3+ regulatory T cells

J Immunol. 2009 Jun 1;182(11):6736-43. doi: 10.4049/jimmunol.0900498.

Abstract

Natural regulatory T cells (nTregs) that develop in the thymus are essential to limit immune responses and prevent autoimmunity. However, the steps necessary for their thymic development are incompletely understood. The CARMA1/Bcl10/Malt1 (CBM) complex, comprised of adaptors that link the TCR to the transcription factor NF-kappaB, is required for development of regulatory T cells (Tregs) but not conventional T cells. Current models propose that TCR-NF-kappaB is needed in a Treg-extrinsic manner for IL-2 production by conventional T cells or in already precommitted Treg precursors for driving IL-2/STAT5 responsiveness and further maturation into Tregs and/or for promoting cell survival. Using CARMA1-knockout mice, our data show instead that the CBM complex is needed in a Treg-intrinsic rather than -extrinsic manner. Constitutive activity of STAT5 or protection from apoptosis by transgenic expression of Bcl2 in developing Tregs is not sufficient to rescue CARMA1-knockout Treg development. Instead, our results demonstrate that the CBM complex controls an early checkpoint in Treg development by enabling generation of thymic precursors of Tregs. These data suggest a modified model of nTreg development in which TCR-CBM-dependent signals are essential to commit immature thymocytes to the nTreg lineage.

Publication types

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

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism*
  • Animals
  • B-Cell CLL-Lymphoma 10 Protein
  • CARD Signaling Adaptor Proteins / physiology*
  • Caspases / metabolism*
  • Cell Cycle*
  • Forkhead Transcription Factors*
  • Mice
  • Mice, Knockout
  • Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein
  • Multiprotein Complexes / immunology
  • Neoplasm Proteins / metabolism*
  • Proto-Oncogene Proteins c-bcl-2
  • STAT5 Transcription Factor
  • T-Lymphocytes, Regulatory / cytology*
  • Thymus Gland / immunology*

Substances

  • Adaptor Proteins, Signal Transducing
  • B-Cell CLL-Lymphoma 10 Protein
  • Bcl10 protein, mouse
  • CARD Signaling Adaptor Proteins
  • Card11 protein, mouse
  • Forkhead Transcription Factors
  • Foxp3 protein, mouse
  • Multiprotein Complexes
  • Neoplasm Proteins
  • Proto-Oncogene Proteins c-bcl-2
  • STAT5 Transcription Factor
  • Caspases
  • Malt1 protein, mouse
  • Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein