title: CD25+CD4+ regulatory T cells prevent graft rejection: CTLA-4- and IL-10-dependent immunoregulation of alloresponses.
abstract: Specific and selective immunological unresponsiveness to donor alloantigens can be induced in vivo. We have shown previously that CD25+CD4+ T cells from mice exhibiting long-term operational tolerance to donor alloantigens can regulate rejection of allogeneic skin grafts mediated by CD45RB(high)CD4+ T cells. In this study, we wished to determine whether donor-specific regulatory cells can be generated during the induction phase of unresponsiveness, i.e., before transplantation. We provide evidence that pretreatment with anti-CD4 Ab plus a donor-specific transfusion generates donor-specific regulatory CD25+CD4+ T cells that can suppress rejection of skin grafts mediated by naive CD45RB(high)CD4+ T cells. Regulatory cells were contained only in the CD25+ fraction, as equivalent numbers of CD25-CD4+ T cells were unable to regulate rejection. This pretreatment strategy led to increased expression of CD122 by the CD25+CD4+ T cells. Blockade of both the IL-10 and CTLA-4 pathways abrogated immunoregulation mediated by CD25+ T cells, suggesting that IL-10 and CTLA-4 are required for the functional activity of this population of immunoregulatory T cells. In clinical transplantation, the generation of regulatory T cells that could provide dynamic control of rejection responses is a possible route to permanent graft survival without the need for long-term immunosuppression.
authors.affiliation: Nuffield Department of Surgery, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DU, United Kingdom.
authors.forename: Cherry I
authors.initials: CI
authors.lastname: Kingsley
authors.forename: Mahzuz
authors.initials: M
authors.lastname: Karim
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Bushell
authors.forename: Kathryn J
authors.initials: KJ
authors.lastname: Wood
mesh_terms: D000069594:Abatacept; D000818:Animals; D000911:Antibodies, Monoclonal / Q000032:analysis; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000096:biosynthesis / Q000502:physiology*; D001803:Blood Transfusion; D015704:CD4 Antigens / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000637:transplantation; D060908:CTLA-4 Antigen; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D006084:Graft Rejection / Q000276:immunology* / Q000517:prevention & control*; D018796:Immunoconjugates; D016753:Interleukin-10 / Q000502:physiology*; D007519:Isoantigens / Q000276:immunology*; D008213:Lymphocyte Activation; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D018345:Mice, Knockout; D015375:Receptors, Interleukin-2 / Q000096:biosynthesis* / Q000502:physiology; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism / Q000637:transplantation; D019172:Transplantation Conditioning; D023001:Transplantation Tolerance
chemical_list: D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D000943:Antigens, Differentiation; D015704:CD4 Antigens; D060908:CTLA-4 Antigen; C556707:Ctla4 protein, mouse; D018984:Epitopes, T-Lymphocyte; D018796:Immunoconjugates; D007519:Isoantigens; D015375:Receptors, Interleukin-2; D016753:Interleukin-10; D000069594:Abatacept