Department of Pathology; Program in Molecular Medicine; Department of Medicine, Division of Pulmonary, Allergy and Critical Care Medicine
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.
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© 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
J Exp Med. 2009 Feb 16;206(2):421-34. Epub 2009 Feb 2. Link to article on publisher's site
The Journal of experimental medicine
Friedline RH, Brown DS, Nguyen H, Kornfeld H, Lee J, Zhang Y, Appleby M, Der SD, Kang J, Chambers CA. (2009). CD4+ regulatory T cells require CTLA-4 for the maintenance of systemic tolerance. Open Access Articles. https://doi.org/10.1084/jem.20081811. Retrieved from https://escholarship.umassmed.edu/oapubs/2155
Creative Commons License
This work is licensed under a Creative Commons Attribution-Noncommercial-Share Alike 3.0 License.