The Journal of Experimental Medicine
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Published 7 March 2005. doi:10.1084/jem.20040685
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 201, Number 5, 737-746
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ARTICLE

 T cells that cannot respond to TGF-ß escape control by CD4+CD25+ regulatory T cells

Linda Fahlén1, Simon Read1, Leonid Gorelik2, Stephen D. Hurst3, Robert L. Coffman4, Richard A. Flavell2, and Fiona Powrie1

1 Sir William Dunn School of Pathology, University of Oxford, Oxford OX1 3RE, England, UK
2 Section of Immunobiology, Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT 06520
3 Department of Immunology, Genentech, South San Francisco, CA 94080
4 Dynavax Technologies Corporation, Berkeley, CA 94710

CORRESPONDENCE Fiona Powrie: fiona.powrie{at}path.ox.ac.uk

CD4+CD25+ regulatory T (T reg) cells play a pivotal role in control of the immune response. Transforming growth factor-ß (TGF-ß) has been shown to be required for T reg cell activity; however, precisely how it is involved in the mechanism of suppression is poorly understood. Using the T cell transfer model of colitis, we show here that CD4+CD45RBhigh T cells that express a dominant negative TGF-ß receptor type II (dnTßRII) and therefore cannot respond to TGF-ß, escape control by T reg cells in vivo. CD4+CD25+ T reg cells from the thymus of dnTßRII mice retain the ability to inhibit colitis, suggesting that T cell responsiveness to TGF-ß is not required for the development or peripheral function of thymic-derived T reg cells. In contrast, T reg cell activity among the peripheral dnTßRII CD4+CD25+ population is masked by the presence of colitogenic effector cells that cannot be suppressed. Finally, we show that CD4+CD25+ T reg cells develop normally in the absence of TGF-ß1 and retain the ability to suppress colitis in vivo. Importantly, the function of TGF-ß1–/– T reg cells was abrogated by anti–TGF-ß monoclonal antibody, indicating that functional TGF-ß can be provided by a non–T reg cell source.

Abbreviations used: dnTßRII, dominant negative TGF-ß receptor II; LP, lamina propria; Tg, transgenic; T reg, regulatory T.

L. Fahlén and S. Read contributed equally to this work.


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