title: Allogeneic stimulation of naturally occurring CD4+CD25+ T cells induces strong regulatory capacity with increased donor-reactivity.
abstract: Current therapies in transplantation require continuous immunosuppression and do not result in transplantation tolerance. It is increasingly appreciated that CD4(+)CD25(+) regulatory T-cell (T(REG)) activation is pivotal for the induction and maintenance of peripheral tolerance. To optimally exploit T(REG) in allograft tolerance, we investigated how to further harness their function. In vitro, CD4(+)CD25(+)T cells were expanded by allogeneic bone-marrow derived DC or polyclonal stimulation and were compared in suppressive capacity and phenotype. In vivo, naive allogeneic CD4(+)CD25(+)T cells were analyzed in wild type hosts for proliferative capacity and suppressive capacity upon priming by alloantigen. DC of donor origin were found to potently stimulate alloreactive T(REG)in vitro. This was accompanied by a substantial enhancement of the suppressive capacity of the T(REG) population as a whole, likely due to a proportional rise of alloreactive T(REG) as indicated by CFSE analysis. In vivo analysis of infused naturally occurring allogeneic T(REG) revealed a robust proliferative capacity for T(REG) upon stimulation. Moreover, allogeneic skin transplantation resulted in enhanced capacity of the T(REG) population to suppress the response towards donor antigens. Combining, activation of alloreactive T(REG) is an intrinsic part of the regular alloimmune response and this feature can be exploited for therapeutic purposes. We propose that selectively favoring the effects of alloreactive T(REG) is a pivotal element in inducing graft acceptance.
authors.affiliation: Department of Bloodtransfusion and Transplantation Immunology, University Medical Center Nijmegen, PO Box 9101, 6500 HB Nijmegen, The Netherlands.
authors.forename: Jeroen J A
authors.initials: JJ
authors.lastname: Coenen
authors.forename: Hans J P M
authors.initials: HJ
authors.lastname: Koenen
authors.forename: Peter M
authors.initials: PM
authors.lastname: Emmer
authors.forename: Esther
authors.initials: E
authors.lastname: van Rijssen
authors.forename: Luuk B
authors.initials: LB
authors.lastname: Hilbrands
authors.forename: Irma
authors.initials: I
authors.lastname: Joosten
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D017951:Antigen Presentation; D017252:CD3 Complex / Q000276:immunology; D015704:CD4 Antigens / Q000032:analysis; D018920:Coculture Techniques; D003713:Dendritic Cells / Q000276:immunology; D053645:Interleukin-2 Receptor alpha Subunit / Q000032:analysis; D007519:Isoantigens / Q000276:immunology*; D051379:Mice; D010641:Phenotype; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology*; D014019:Tissue Donors; D023001:Transplantation Tolerance / Q000187:drug effects / Q000276:immunology*
chemical_list: D000911:Antibodies, Monoclonal; D017252:CD3 Complex; D015704:CD4 Antigens; D053645:Interleukin-2 Receptor alpha Subunit; D007519:Isoantigens