title: Blockade of CTLA-4 on CD4+CD25+ regulatory T cells abrogates their function in vivo.
abstract: 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.affiliation: Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford, United Kingdom.
authors.forename: Simon
authors.initials: S
authors.lastname: Read
authors.forename: Rebecca
authors.initials: R
authors.lastname: Greenwald
authors.forename: Ana
authors.initials: A
authors.lastname: Izcue
authors.forename: Nicholas
authors.initials: N
authors.lastname: Robinson
authors.forename: Didier
authors.initials: D
authors.lastname: Mandelbrot
authors.forename: Loise
authors.initials: L
authors.lastname: Francisco
authors.forename: Arlene H
authors.initials: AH
authors.lastname: Sharpe
authors.forename: Fiona
authors.initials: F
authors.lastname: Powrie
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000276:immunology* / Q000378:metabolism; D018122:B7-1 Antigen / Q000276:immunology / Q000378:metabolism; D051940:B7-2 Antigen / Q000276:immunology / Q000378:metabolism; D015704:CD4 Antigens / Q000276:immunology / Q000378:metabolism*; D060908:CTLA-4 Antigen; D003092:Colitis / Q000276:immunology; D004195:Disease Models, Animal; D005434:Flow Cytometry; D007422:Intestines / Q000276:immunology; D008221:Lymphoid Tissue / Q000166:cytology / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D015375:Receptors, Interleukin-2 / Q000276:immunology / Q000378:metabolism*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
chemical_list: D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D000943:Antigens, Differentiation; D018122:B7-1 Antigen; D051940:B7-2 Antigen; D015704:CD4 Antigens; D060908:CTLA-4 Antigen; C556707:Ctla4 protein, mouse; D015375:Receptors, Interleukin-2