title: Allogeneic T regulatory cell-mediated transplantation tolerance in adoptive therapy depends on dominant peripheral suppression and central tolerance.
abstract: T regulatory cells (Tregs) represent agents to mediate tolerance to allografts so that the use of immunosuppressive drugs is avoided. In this regard, we previously demonstrated that the adoptive transfer of allogeneic Tregs into IL-2Rbeta(-/-) mice prevented autoimmunity and led to allograft tolerance. Here, we investigated the requirements and mechanisms that favor this long-lasting tolerance. The most potent tolerance required exact matching of all alloantigens between the adoptively transferred allogeneic Tregs and allogeneic skin grafts, but tolerance to such allografts that lacked expression of major histocompatibility complex class I or II molecules also occurred. Thus, Tregs are not required to directly recognize major histocompatibility complex class II alloantigens to suppress skin transplant rejection. Depletion of allogeneic Tregs substantially, but not completely, abrogated this form of tolerance. However, thymocytes from allogeneic Treg adoptively transferred IL-2Rbeta(-/-) mice did not reject the corresponding allogeneic skin graft in secondary Scid recipients. Consistent with a requirement for a deletional mechanism in this IL-2Rbeta(-/-) model, a small number of wild-type T cells readily abrogated the immune tolerant state. Collectively, these findings indicate that full tolerance induction is largely dependent on substantial Treg-mediated suppression and thymic deletion of alloreactive T cells and may represent general conditions for Treg-mediated transplantation tolerance.
authors.affiliation: Department of Microbiology and Immunology, Miller School of Medicine, University of Miami, 1600 NW 10th Ave, Miami, FL 33136, USA.
authors.forename: Dennis
authors.initials: D
authors.lastname: Adeegbe
authors.forename: Robert B
authors.initials: RB
authors.lastname: Levy
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Malek
mesh_terms: D000818:Animals; D015395:Histocompatibility Antigens Class I / Q000378:metabolism; D000949:Histocompatibility Antigens Class II / Q000378:metabolism; D007108:Immune Tolerance / Q000276:immunology; D007165:Immunosuppression Therapy / Q000379:methods*; D016219:Immunotherapy, Adoptive / Q000379:methods*; D053646:Interleukin-2 Receptor beta Subunit / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016513:Mice, SCID; D016038:Skin Transplantation / Q000276:immunology / Q000502:physiology; D050378:T-Lymphocytes, Regulatory / Q000502:physiology / Q000637:transplantation*; D023001:Transplantation Tolerance / Q000276:immunology*; D014184:Transplantation, Homologous
chemical_list: D015395:Histocompatibility Antigens Class I; D000949:Histocompatibility Antigens Class II; C508022:Il2rb protein, mouse; D053646:Interleukin-2 Receptor beta Subunit