Blockade of CTLA-4 on CD4+CD25+ regulatory T cells abrogates their function in vivo.

Journal article

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.

Authors: Read, S; Greenwald, R; Izcue, A; Robinson, N; Mandelbrot, D

• Publication status: Published
• Journal: Journal of Immunology
• Volume: 177
• Issue: 7
• Pages: 4376-4383
• Publication date: 2006-10-01
• DOI: 10.4049/jimmunol.177.7.4376
• EISSN: 1550-6606
• ISSN: 0022-1767
• Language: English
• Keywords: Antigens, CD4; Disease Models, Animal; Antigens, Differentiation; Antigens, CD86; Mice; Animals; Intestines; CTLA-4 Antigen; Mice, Inbred BALB C; Colitis; Mice, Knockout; Antigens, CD; T-Lymphocytes, Regulatory; Receptors, Interleukin-2; Flow Cytometry; Antigens, CD80; Antibodies, Monoclonal; Lymphoid Tissue