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Randall H. Friedline¹, David S. Brown¹, Hai Nguyen¹, Hardy Kornfeld², JinHee Lee², Yi Zhang³, Mark Appleby⁴, Sandy D. Der⁵, Joonsoo Kang¹, and Cynthia A. Chambers^1,

¹ Department of Pathology, ² Department of Medicine, Graduate Program in Immunology and Virology, University of Massachusetts Medical School, Worcester, MA 01655
³ Amgen, Inc., South San Francisco, CA 94080
⁴ Zymogenetics, Inc., Seattle, WA 98102
⁵ Department of Laboratory Medicine and Pathobiology, Program in Proteomics and Bioinformatics, University of Toronto, M5S 3G4 Toronto, Canada

CORRESPONDENCE Joonsoo Kang: Joonsoo.Kang{at}umassmed.edu

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.

C.A. Chambers died on December 19, 2004.

© 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/).

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