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

UMMS Affiliation

Department of Pathology; Program in Molecular Medicine; Department of Medicine, Division of Pulmonary, Allergy and Critical Care Medicine

Publication Date


Document Type



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


Life Sciences | Medicine and Health Sciences


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.

DOI of Published Version



J Exp Med. 2009 Feb 16;206(2):421-34. Epub 2009 Feb 2. Link to article on publisher's site

Journal/Book/Conference Title

The Journal of experimental medicine

Related Resources

Link to Article in PubMed

PubMed ID