title: Intracellular MHC class II controls regulatory tolerance to allogeneic transplants.
abstract: MHC class II (MHCII) genes have been implicated in the regulation of T lymphocyte responses. However, the mechanism of MHCII-driven regulation remains unknown. Matching for MHCII between donors and recipients of allografts favors regulatory T cell tolerance to transplants and provides a unique opportunity to study this regulation. In this study, we investigated MHCII regulation using transfer of donor MHCII genes in recipients of cardiac allografts. Transfer of MHCII IA(b) genes in the bone marrow of CBA mice (H-2(k)) prior to the grafting of IA(b+) fully allogeneic C57BL/6 (B6, H-2(b)) heart transplants resulted in donor-specific tolerance associated with long-term survival of B6, but not third-party, allografts without sustained immunosuppression. Strikingly, the majority of accepted heart transplants (>170 d) were devoid of allograft vasculopathy. Further studies indicated that intracellular IA(b) initiated the tolerogenic process, which was mediated by regulatory T cells (Tregs) that polarized antigraft responses to Th2 cytokine producers. This mechanism seems to be unique to MHCII genes, because previous MHC class I gene-based therapies failed to produce Tregs. These results demonstrate the key role of MHCII in the induction of Tregs. They also underscore a potential mechanism of specific inactivation of T cells in this model; when activated by IA(b+) grafts, IA(b)-specific Tregs repress the entire alloresponse to C57BL/6 transplants (including MHC I and minor Ags), thus mediating T cell tolerance.
authors.affiliation: Laboratory of Molecular Biology, Transplantation Biology Research Center, Massachusetts General Hospital, MGH-East, Building 149-9019, 13th Street, Boston, MA 02129, USA. christian.leguern@tbrc.mgh.harvard.edu
authors.forename: Christian
authors.initials: C
authors.lastname: LeGuern
authors.forename: Yoshinobu
authors.initials: Y
authors.lastname: Akiyama
authors.forename: Sharon
authors.initials: S
authors.lastname: Germana
authors.forename: Katsunori
authors.initials: K
authors.lastname: Tanaka
authors.forename: Luis
authors.initials: L
authors.lastname: Fernandez
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Iwamoto
authors.forename: Stuart
authors.initials: S
authors.lastname: Houser
authors.forename: Gilles
authors.initials: G
authors.lastname: Benichou
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology / Q000378:metabolism*; D016026:Bone Marrow Transplantation; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D005260:Female; D005822:Genetic Vectors / Q000235:genetics; D006085:Graft Survival / Q000235:genetics / Q000276:immunology; D016027:Heart Transplantation / Q000379:methods*; D000949:Histocompatibility Antigens Class II / Q000235:genetics / Q000276:immunology*; D042541:Intracellular Space / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D012190:Retroviridae / Q000235:genetics; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D014161:Transduction, Genetic; D023001:Transplantation Tolerance / Q000276:immunology*; D014184:Transplantation, Homologous
chemical_list: D000949:Histocompatibility Antigens Class II