title: Adoptive transfer of double negative T regulatory cells induces B-cell death in vivo and alters rejection pattern of rat-to-mouse heart transplantation.
abstract: BACKGROUND
  Antibody-mediated hyperacute and acute graft rejection are major obstacles in achieving long-term graft survival in xenotransplantation. It is well documented that regulatory T (Treg) cells play a very important role in regulating immune responses to self and non-self antigens. Our previous studies have shown that TCRalphabeta+CD3+CD4-CD8- (double negative, DN)-Treg cells can suppress anti-donor T-cell responses and prolong graft survival in allo- and xenotransplantation models. We have demonstrated that DN-Treg cells can induce B-cell apoptosis in vitro through a perforin-dependent pathway.
  
  
  METHODS
  B6 mice received rat heart grafts, followed by 14 days of LF15-0195 treatment. Some mice received Lewis rat cell activated DN-Treg cells after LF treatment. DN-Treg cells, purified from perforin-/- mice and from B6 mice pre-immunized with third party rat cells, were used as controls.
  
  
  RESULTS
  In this study, we investigated the possibility that adoptive transfer of xenoreactive DN-Treg cells could suppress B cells in vivo, thus prolonging xenograft survival. We found that apoptotic death of B cells significantly increased after adoptive transfer of DN-Treg cells. In addition, anti-donor IgG subtypes were significantly inhibited in the DN-Treg cell-treated group, in which the rejection pattern was altered towards cellular-mediated rejection rather than antibody-mediated acute vascular rejection. However, perforin-deficient DN-Treg cells failed to induce B-cell death and to prolong heart graft survival, indicating a perforin-dependent mechanism contributes to B-cell death in vivo.
  
  
  CONCLUSIONS
  This study suggests that adoptive transfer of xenoreactive DN-Treg cells can inhibit B-cell responses in vivo. DN-Treg cells may be valuable in controlling B-cell responses in xenotransplantation.
authors.affiliation: Immunology and Transplantation, Lawson Health Research Institute, London, Ontario, Canada.
authors.forename: Yuexia
authors.initials: Y
authors.lastname: Ma
authors.forename: Kathy M
authors.initials: KM
authors.lastname: He
authors.forename: Bertha
authors.initials: B
authors.lastname: Garcia
authors.forename: Weiping
authors.initials: W
authors.lastname: Min
authors.forename: Anthony
authors.initials: A
authors.lastname: Jevnikar
authors.forename: Zhu-Xu
authors.initials: ZX
authors.lastname: Zhang
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology*; D016923:Cell Death / Q000502:physiology*; D006084:Graft Rejection; D006085:Graft Survival; D016027:Heart Transplantation / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D054353:Perforin / Q000235:genetics / Q000378:metabolism; D051381:Rats; D011917:Rats, Inbred Lew; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D014183:Transplantation, Heterologous
chemical_list: D054353:Perforin