title: NK cells contribute to the skin graft rejection promoted by CD4+ T cells activated through the indirect allorecognition pathway.
abstract: Rejection of solid organ allografts is promoted by T cells. Recipient T cells can directly recognize intact allo-MHC molecules on donor cells and can also indirectly recognize processed donor-derived allo-peptides presented by recipient antigen-presenting cells in the context of self-MHC molecules. Although CD4(+) T cells primed through the indirect allorecognition pathway alone are sufficient to promote acute allograft rejection, it is unknown how they can mediate graft destruction without cognate recognition of donor cells. In this study, we analyzed the indirect effector mechanism of skin allograft rejection using a mouse model in which SCID recipients bearing MHC class II-deficient skin allografts were adoptively transferred with CD4(+) T cells. Histologically, entire graft necrosis was preceded by mononuclear cell infiltration in the graft epithelia with epithelial cell apoptosis, indicating cell-mediated cytotoxicity against donor cells as an effector mechanism. Beside CD4(+) T cells and macrophages, NK cells infiltrated in the rejecting grafts. Depletion of NK cells as well as blocking of the activating NK receptor NKG2D allowed prolonged survival of the grafts. Expression of NKG2D ligands was up-regulated in the rejecting grafts. These results suggest that NK cells activated through NKG2D contribute to the skin allograft rejection promoted by indirectly primed CD4(+) T cells.
authors.affiliation: Division of Dermatology, Niigata University Graduate School of Medical and Dental Sciences, Niigata 951-8510, Japan.
authors.forename: Akiko
authors.initials: A
authors.lastname: Ito
authors.forename: Hideki
authors.initials: H
authors.lastname: Shimura
authors.forename: Ayano
authors.initials: A
authors.lastname: Nitahara
authors.forename: Katsuhiro
authors.initials: K
authors.lastname: Tomiyama
authors.forename: Masaaki
authors.initials: M
authors.lastname: Ito
authors.forename: Takuro
authors.initials: T
authors.lastname: Kanekura
authors.forename: Ko
authors.initials: K
authors.lastname: Okumura
authors.forename: Hideo
authors.initials: H
authors.lastname: Yagita
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Kawai
mesh_terms: D000818:Animals; D019138:Antibodies, Blocking / Q000008:administration & dosage / Q000276:immunology; D017951:Antigen Presentation / Q000235:genetics / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D045142:Cross-Priming; D005260:Female; D005802:Genes, MHC Class II / Q000235:genetics / Q000276:immunology; D006084:Graft Rejection / Q000276:immunology*; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D008213:Lymphocyte Activation / Q000276:immunology*; D008212:Lymphocyte Depletion; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D016513:Mice, SCID; D055655:NK Cell Lectin-Like Receptor Subfamily K; D011971:Receptors, Immunologic / Q000037:antagonists & inhibitors; D055607:Receptors, Natural Killer Cell; D016038:Skin Transplantation / Q000276:immunology* / Q000473:pathology; D014181:Transplantation Immunology; D014184:Transplantation, Homologous
chemical_list: D019138:Antibodies, Blocking; C527086:Klrk1 protein, mouse; D055655:NK Cell Lectin-Like Receptor Subfamily K; D011971:Receptors, Immunologic; D055607:Receptors, Natural Killer Cell