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Naturally occurring CD4+ regulatory T cells (T(R)) 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 T(R) in experimental and clinical analysis. However, it has not yet been proven that CTLA-4 has a direct role in T(R) function. In this study, using a T cell-mediated colitis model, we demonstrate that anti-CTLA-4 mAb treatment inhibits T(R) function in vivo via direct effects on CTLA-4-expressing T(R), and not via hyperactivation of colitogenic effector T cells. Although anti-CTLA-4 mAb treatment completely inhibits T(R) function, it does not reduce T(R) numbers or their homing to the GALT, suggesting the Ab mediates its function by blockade of a signal required for T(R) activity. In contrast to the striking effect of the Ab, CTLA-4-deficient mice can produce functional T(R), 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 T(R). 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 T(R)-mediated self-tolerance.

Original publication

DOI

10.4049/jimmunol.177.7.4376

Type

Journal article

Journal

Journal of immunology (Baltimore, Md. : 1950)

Publication Date

10/2006

Volume

177

Pages

4376 - 4383

Addresses

Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford, United Kingdom.

Keywords

Intestines, Lymphoid Tissue, Animals, Mice, Inbred BALB C, Mice, Knockout, Mice, Colitis, Disease Models, Animal, Receptors, Interleukin-2, Antigens, CD4, Antigens, Differentiation, Antigens, CD, Antigens, CD80, Antibodies, Monoclonal, Flow Cytometry, T-Lymphocytes, Regulatory, Antigens, CD86, CTLA-4 Antigen