title: Depletion of foxp3(+) T cells abrogates tolerance of skin and heart allografts in murine mixed chimeras without the loss of mixed chimerism.
abstract: The relative contribution of central and peripheral mechanisms to the generation and maintenance of allograft tolerance is of considerable interest. Here, we present new evidence that regulatory T cells (Foxp3(+) ) maintain skin and heart allograft tolerance in mixed hematopoietic chimeric mice. Transient depletion of both donor- and recipient-derived Foxp3(+) cells was necessary and sufficient to induce decisive rejection of long-accepted skin and heart allografts. In contrast, stable hematopoietic chimerism remained, and there was no detectable induction of donor-specific reactivity to hematopoietic cells. Foxp3(+) cell depletion did not result in the rejection of skin grafts of only MHC-disparate donors (B6.C-H2(d) /bByJ), indicating that MHC antigens were not the target in the graft. We conclude that two different mechanisms of tolerance are present in mixed chimeras. Hematopoietic chimerism, resistant to Foxp3(+) depletion, is probably due to deletional tolerance to MHC antigens, as supported by previous studies. In contrast, regulatory tolerance mechanisms involving Foxp3(+) cells are required to control reactivity against non-MHC antigens not present on hematopoietic lineages.
authors.affiliation: Transplant Center, Massachusetts General Hospital, Boston, MA.|Department of Surgery, Massachusetts General Hospital, Boston, MA.
authors.forename: K
authors.initials: K
authors.lastname: Shinoda
authors.affiliation: Department of Pathology, Massachusetts General Hospital, Boston, MA.
authors.forename: T
authors.initials: T
authors.lastname: Akiyoshi
authors.affiliation: Transplant Center, Massachusetts General Hospital, Boston, MA.|Department of Surgery, Massachusetts General Hospital, Boston, MA.
authors.forename: C M
authors.initials: CM
authors.lastname: Chase
authors.affiliation: Department of Pathology, Massachusetts General Hospital, Boston, MA.
authors.forename: E A
authors.initials: EA
authors.lastname: Farkash
authors.affiliation: Department of Pathology, Massachusetts General Hospital, Boston, MA.
authors.forename: D K
authors.initials: DK
authors.lastname: Ndishabandi
authors.affiliation: Department of Pathology, Massachusetts General Hospital, Boston, MA.
authors.forename: C M
authors.initials: CM
authors.lastname: Raczek
authors.affiliation: Department of Pathology, Massachusetts General Hospital, Boston, MA.
authors.forename: D P
authors.initials: DP
authors.lastname: Sebastian
authors.affiliation: Department of Pathology, Massachusetts General Hospital, Boston, MA.
authors.forename: P Della
authors.initials: PD
authors.lastname: Pelle
authors.affiliation: Transplant Center, Massachusetts General Hospital, Boston, MA.|Department of Surgery, Massachusetts General Hospital, Boston, MA.|Department of Surgery, Harvard Medical School, Boston, MA.
authors.forename: P S
authors.initials: PS
authors.lastname: Russell
authors.affiliation: Transplant Center, Massachusetts General Hospital, Boston, MA.|Department of Surgery, Massachusetts General Hospital, Boston, MA.|Department of Surgery, Harvard Medical School, Boston, MA.
authors.forename: J C
authors.initials: JC
authors.lastname: Madsen
authors.affiliation: Transplant Center, Massachusetts General Hospital, Boston, MA.|Department of Pathology, Massachusetts General Hospital, Boston, MA.|Department of Pathology, Harvard Medical School, Boston, MA.
authors.forename: R B
authors.initials: RB
authors.lastname: Colvin
authors.affiliation: Transplant Center, Massachusetts General Hospital, Boston, MA.|Department of Surgery, Massachusetts General Hospital, Boston, MA.|Department of Surgery, Harvard Medical School, Boston, MA.
authors.forename: A
authors.initials: A
authors.lastname: Alessandrini
mesh_terms: D000818:Animals; D002678:Chimera; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D051858:Forkhead Transcription Factors / Q000276:immunology*; D006084:Graft Rejection / Q000276:immunology; D016027:Heart Transplantation; D007108:Immune Tolerance; D008212:Lymphocyte Depletion; D051379:Mice; D016038:Skin Transplantation; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse
keywords: Basic (laboratory) research/science; bone marrow/hematopoietic stem cell transplantation; heart transplantation/cardiology; immunobiology; major histocompatibility complex (MHC); tolerance: chimerism; tolerance: mechanisms