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CD4+ regulatory T cells require CTLA-4 for the maintenance of systemic tolerance.

Cytotoxic T lymphocyte antigen-4 (CTLA-4) plays a critical role in negatively regulating T cell responses and has also been implicated in the development and function of natural FOXP3(+) regulatory T cells. CTLA-4-deficient mice develop fatal, early onset lymphoproliferative disease. However, chimeric mice containing both CTLA-4-deficient and -sufficient bone marrow (BM)-derived cells do not develop disease, indicating that CTLA-4 can act in trans to maintain T cell self-tolerance. Using genetically mixed blastocyst and BM chimaeras as well as in vivo T cell transfer systems, we demonstrate that in vivo regulation of Ctla4(-/-) T cells in trans by CTLA-4-sufficient T cells is a reversible process that requires the persistent presence of FOXP3(+) regulatory T cells with a diverse TCR repertoire. Based on gene expression studies, the regulatory T cells do not appear to act directly on T cells, suggesting they may instead modulate the stimulatory activities of antigen-presenting cells. These results demonstrate that CTLA-4 is absolutely required for FOXP3(+) regulatory T cell function in vivo.

Pubmed ID: 19188497


  • Friedline RH
  • Brown DS
  • Nguyen H
  • Kornfeld H
  • Lee J
  • Zhang Y
  • Appleby M
  • Der SD
  • Kang J
  • Chambers CA


The Journal of experimental medicine

Publication Data

February 16, 2009

Associated Grants

  • Agency: NIAID NIH HHS, Id: AI054670
  • Agency: NIAID NIH HHS, Id: AI59880

Mesh Terms

  • Adoptive Transfer
  • Animals
  • Antigens, CD
  • Bromodeoxyuridine
  • CTLA-4 Antigen
  • DNA Primers
  • Flow Cytometry
  • Forkhead Transcription Factors
  • Gene Expression Regulation
  • Mice
  • Mice, Knockout
  • Reverse Transcriptase Polymerase Chain Reaction
  • Self Tolerance
  • T-Lymphocytes, Regulatory