title: Deletion of CD98 heavy chain in T cells results in cardiac allograft acceptance by increasing regulatory T cells.
abstract: BACKGROUND
  Little is known about the CD98 heavy chain (CD98hc) in the T lymphocyte-mediated immune response to alloantigen.
  
  
  METHODS
  We used an in vitro mixed leukocyte reaction assay and a cardiac transplantation model to evaluate the mechanisms of CD98hc in regulating alloimmune responses.
  
  
  RESULTS
  A T cell-specific deficiency of CD98hc resulted in lower responses to alloantigen stimulation in a mixed leukocyte reaction assay, and CD98hc-deficient mice accepted full major histocompatibility complex-mismatched cardiac allografts. Consistent with graft survival, the infiltration of the graft by immune cells in CD98hc-deficient mice was significantly lower than that in wild-type mice. A chemotaxis assay revealed the migration of CD98hc-deficient lymphocytes to decrease in the presence of CCL5 compared with wild-type cells. Moreover, the proportion of CD4/Foxp3-positive cells and Foxp3 messenger RNA increased significantly in CD98hc-deficient recipients, consistent with the down-regulation of mammalian target of rapamycin and PS6 kinase; and allograft permanent acceptance was shortened by the depletion of antibody-induced regulatory T cells. Finally, neutralizing antibody against CD98hc prolonged the cardiac allograft survival.
  
  
  CONCLUSIONS
  Taken together, our data indicate that T cell-specific deficiency in CD98hc can contribute to cardiac allograft permanent acceptance correlating with the attenuation of lymphocyte migration and by increasing the generation of regulatory T cells. These findings are expected to make it possible to develop novel approaches for treating allograft rejection and promoting transplantation tolerance.
authors.affiliation: Division of Radiation Safety and Immune Tolerance, National Research Institute for Child Health and Development, Tokyo, Japan.
authors.forename: Zhong
authors.initials: Z
authors.lastname: Liu
authors.forename: Jiangang
authors.initials: J
authors.lastname: Hou
authors.forename: Jiajie
authors.initials: J
authors.lastname: Chen
authors.forename: Hideki
authors.initials: H
authors.lastname: Tsumura
authors.forename: Morihiro
authors.initials: M
authors.lastname: Ito
authors.forename: Yasuhiko
authors.initials: Y
authors.lastname: Ito
authors.forename: Xiang
authors.initials: X
authors.lastname: Hu
authors.forename: Xiao-Kang
authors.initials: XK
authors.lastname: Li
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D001483:Base Sequence; D027282:Fusion Regulatory Protein 1, Heavy Chain / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D006084:Graft Rejection / Q000276:immunology / Q000517:prevention & control*; D006085:Graft Survival / Q000276:immunology*; D016027:Heart Transplantation / Q000276:immunology* / Q000401:mortality; D007519:Isoantigens / Q000276:immunology; D053208:Kaplan-Meier Estimate; D007962:Leukocytes / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017384:Sequence Deletion; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism; D014184:Transplantation, Homologous / Q000276:immunology
chemical_list: D000911:Antibodies, Monoclonal; D027282:Fusion Regulatory Protein 1, Heavy Chain; D007519:Isoantigens; C523212:Slc3A2 protein, mouse