UMMS Affiliation

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

Publication Date

2009-02-04

Document Type

Article

Subjects

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

Disciplines

Life Sciences | Medicine and Health Sciences

Abstract

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.

Rights and Permissions

© 2009 Friedline et al. This article is distributed under the terms of an Attribution– Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.jem.org/misc/terms.shtml). After six months it is available under a Creative Commons License (Attribution–Noncommercial– Share Alike 3.0 Unported license, as described at http://creativecommons. org/licenses/by-nc-sa/3.0/).

DOI of Published Version

10.1084/jem.20081811

Source

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

19188497

Creative Commons License

Creative Commons Attribution-Noncommercial-Share Alike 3.0 License
This work is licensed under a Creative Commons Attribution-Noncommercial-Share Alike 3.0 License.

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