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* Sir William Dunn School of Pathology, University of Oxford, Oxford, United Kingdom; and
Department of Pathology, Harvard Medical School, Brigham and Women’s Hospital, Boston, MA 02115
Naturally occurring CD4+ regulatory T cells (TR) that express CD25 and the transcription factor FoxP3 play a key role in immune homeostasis, preventing immune pathological responses to self and foreign Ags. CTLA-4 is expressed by a high percentage of these cells, and is often considered as a marker for TR in experimental and clinical analysis. However, it has not yet been proven that CTLA-4 has a direct role in TR function. In this study, using a T cell-mediated colitis model, we demonstrate that anti-CTLA-4 mAb treatment inhibits TR function in vivo via direct effects on CTLA-4-expressing TR, and not via hyperactivation of colitogenic effector T cells. Although anti-CTLA-4 mAb treatment completely inhibits TR function, it does not reduce TR numbers or their homing to the GALT, suggesting the Ab mediates its function by blockade of a signal required for TR activity. In contrast to the striking effect of the Ab, CTLA-4-deficient mice can produce functional TR, suggesting that under some circumstances other immune regulatory mechanisms, including the production of IL-10, are able to compensate for the loss of the CTLA-4-mediated pathway. This study provides direct evidence that CTLA-4 has a specific, nonredundant role in the function of normal TR. This role has to be taken into account when targeting CTLA-4 for therapeutic purposes, as such a strategy will not only boost effector T cell responses, but might also break TR-mediated self-tolerance.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 S.R., N.R., and F.P. were funded by the Wellcome Trust. A.I. is a recipient of a postdoctoral grant from the Spanish Ministerio de Educación y Ciencia. A.H.S. is the recipient of National Institutes of Health Grants R01 AI40614 and AI38310.
2 Address correspondence and reprint requests to Prof. Fiona Powrie, Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford OX1 3RE, U.K. E-mail address: fiona.powrie{at}path.ox.ac.uk
3 Abbreviations used in this paper: IBD, inflammatory bowel disease; TR, regulatory T cell; WT, wild type; KO, knockout; MLN, mesenteric lymph node.
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