title: Inhibition of swine leukocyte antigen-I presentation in transgenic mini-pig cell lines by expressing human cytomegalovirus US6.
abstract: Xenotransplantation using porcine organs may resolve the chronic shortage of donor organs for clinical transplantation if significant immunologic barriers can be overcome. A xenograft can be rejected by T cells, especially CD8(+) cytotoxic T lymphocytes (CTL)-mediated responses, as these cells show cytotoxicity against xenografts by recognition of swine leukocyte antigen (SLA)-I. Peptide translocation is inhibited by the endoplasmic reticulum-resident human cytomegalovirus (HCMV) glycoprotein unique short (US) 6, due to alterations of the transporter associated with antigen processing loading onto MHC class I for antigen presentation to CD8(+) CTL. In this study we transfected the US6 gene into minipig fetal fibroblasts establishing three US6 clonal cell lines. Flow cytometry analysis of US6 clonal cell lines demonstrated a substantial reduction in SLA-I expression. The level of SLA-I expression in US6 clones was decreased to 56.3% compared with the control 42.7%. In CTL assays, the rate of CD8(+) CTL-mediated cytotoxicity was significantly reduced to 35.2% ± 11.7% compared with the control, 79.9% ± 6.5%, (P < .01). These results suggested that HCMV viral protein US6 suppresses the presentation of SLA-I on pig fetal fibroblast cells. This strategy might be used in transgenic pig production to protect porcine organs from CTL-mediated immune rejection.
authors.affiliation: MGEN, Inc., Seoul, Korea.
authors.forename: J Y
authors.initials: JY
authors.lastname: Yoo
authors.forename: K M
authors.initials: KM
authors.lastname: Choi
authors.forename: S P
authors.initials: SP
authors.lastname: Hong
authors.forename: S H
authors.initials: SH
authors.lastname: Kim
authors.forename: K-W
authors.initials: KW
authors.lastname: Park
authors.forename: J G
authors.initials: JG
authors.lastname: Seol
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D002460:Cell Line; D015395:Histocompatibility Antigens Class I; D000949:Histocompatibility Antigens Class II / Q000276:immunology*; D006801:Humans; D016601:RNA-Binding Proteins / Q000235:genetics*; D013552:Swine; D013556:Swine, Miniature; D013602:T-Lymphocytes, Cytotoxic / Q000166:cytology / Q000276:immunology; D014764:Viral Proteins / Q000235:genetics*
chemical_list: D015395:Histocompatibility Antigens Class I; D000949:Histocompatibility Antigens Class II; D016601:RNA-Binding Proteins; C432877:US6 protein, Human cytomegalovirus; D014764:Viral Proteins; C438668:swine leukocyte antigen