title: Spontaneous allograft tolerance in B7-deficient mice independent of preexisting endogenous CD4+CD25+ regulatory T-cells.
abstract: BACKGROUND
  Acute cardiac allograft rejection requires host, but not donor, expression of B7-1/B7-2 costimulatory molecules. However, acute cardiac rejection requires direct antigen presentation by donor-derived antigen presenting cells to CD4 T-cells and does not require indirect antigen presentation to CD4 T-cells. Given this discrepancy in the literature and that the consequence of allograft exposure in B7-deficient mice is unknown; the goal of the study was to examine the antidonor status of allografted B7-1/B7-2-deficient hosts.
  
  
  METHODS
  C57Bl/6 B7-1/B7-2-/- mice were grafted with heterotopic BALB/c hearts. Recipients bearing long-term surviving allografts were used to examine the status of antidonor reactivity in vitro and in vivo. Tolerance was examined in vivo through adoptive transfer of splenocytes from graft-bearing animals to secondary immune-deficient Rag-1-/- hosts bearing donor-type or third-party cardiac allografts and by regulatory T-cell depletion with anti-CD25 antibody.
  
  
  RESULTS
  When transferred to B7-replete Rag-1-/- recipients, cells from naïve B7-1/B7-2-/- mice readily initiated cardiac allograft rejection. However, splenocytes transferred from long-term allograft acceptor B7-1/B7-2-/- hosts failed to reject donor-type hearts but acutely rejected third-party allografts. In addition, such cells did not reject (donorxthird-party) F1 allografts. Finally, in vivo depletion of regulatory T-cells did not prevent long-term acceptance.
  
  
  CONCLUSIONS
  Results demonstrate that B7-deficient T-cells are capable of acute cardiac allograft rejection in a B7-replete environment. Importantly, results also show that B7-deficient hosts do not simply ignore cardiac allografts, but rather spontaneously develop transferable, donor-specific tolerance and linked suppression in vivo. Interestingly, this tolerant state does not require endogenous CD4+CD25+ regulatory T-cells.
authors.affiliation: Department of Medicine, Division of Pulmonary and Critical Care Medicine, University of Colorado Health Sciences Center, and the Children's Hospital, Denver, CO 80262, USA. Todd.Grazia@uchsc.edu
authors.forename: Todd J
authors.initials: TJ
authors.lastname: Grazia
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Plenter
authors.forename: An N
authors.initials: AN
authors.lastname: Doan
authors.forename: Brian P
authors.initials: BP
authors.lastname: Kelly
authors.forename: Sarah M
authors.initials: SM
authors.lastname: Weber
authors.forename: Jonathan S
authors.initials: JS
authors.lastname: Kurche
authors.forename: Susan O
authors.initials: SO
authors.lastname: Cushing
authors.forename: Ronald G
authors.initials: RG
authors.lastname: Gill
authors.forename: Biagio A
authors.initials: BA
authors.lastname: Pietra
mesh_terms: D000818:Animals; D018122:B7-1 Antigen / Q000235:genetics / Q000378:metabolism*; D051940:B7-2 Antigen / Q000235:genetics / Q000378:metabolism*; D051858:Forkhead Transcription Factors / Q000378:metabolism; D006084:Graft Rejection / Q000473:pathology; D006085:Graft Survival; D016027:Heart Transplantation / Q000276:immunology*; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D007108:Immune Tolerance; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009206:Myocardium / Q000473:pathology; D013154:Spleen / Q000276:immunology / Q000473:pathology; D050378:T-Lymphocytes, Regulatory / Q000378:metabolism*; D013997:Time Factors; D019172:Transplantation Conditioning; D016042:Transplantation, Heterotopic; D014184:Transplantation, Homologous
chemical_list: D018122:B7-1 Antigen; D051940:B7-2 Antigen; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D018398:Homeodomain Proteins; D053645:Interleukin-2 Receptor alpha Subunit; C064658:RAG-1 protein