title: Genetic investigation of MHC-independent missing-self recognition by mouse NK cells using an in vivo bone marrow transplantation model.
abstract: MHC-I-specific receptors play a vital role in NK cell-mediated "missing-self" recognition, which contributes to NK cell activation. In contrast, MHC-independent NK recognition mechanisms are less well characterized. In this study, we investigated the role of NKR-P1B:Clr-b (Klrb1:Clec2d) interactions in determining the outcome of murine hematopoietic cell transplantation in vivo. Using a competitive transplant assay, we show that Clr-b(-/-) bone marrow (BM) cells were selectively rejected by wild-type B6 recipients, to a similar extent as H-2D(b-/-) MHC-I-deficient BM cells. Selective rejection of Clr-b(-/-) BM cells was mitigated by NK depletion of recipient mice. Competitive rejection of Clr-b(-/-) BM cells also occurred in allogeneic transplant recipients, where it was reversed by selective depletion of NKR-P1B(hi) NK cells, leaving the remaining NKR-P1B(lo) NK subset and MHC-I-dependent missing-self recognition intact. Moreover, competitive rejection of Clr-b(-/-) hematopoietic cells was abrogated in Nkrp1b-deficient recipients, which lack the receptor for Clr-b. Of interest, similar to MHC-I-deficient NK cells, Clr-b(-/-) NK cells were hyporesponsive to both NK1.1 (NKR-P1C)-stimulated and IL-12/18 cytokine-primed IFN-γ production. These findings support a unique and nonredundant role for NKR-P1B:Clr-b interactions in missing-self recognition of normal hematopoietic cells and suggest that optimal BM transplant success relies on MHC-independent tolerance mechanisms. These findings provide a model for human NKR-P1A:LLT1 (KLRB1:CLEC2D) interactions in human hematopoietic cell transplants.
authors: Department of Immunology, Sunnybrook Research Institute, University of Toronto, Toronto, Ontario M4N 3M5, Canada;
authors: Peter
authors: P
authors: Chen
authors: Department of Immunology, Sunnybrook Research Institute, University of Toronto, Toronto, Ontario M4N 3M5, Canada;
authors: Oscar A
authors: OA
authors: Aguilar
authors: Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, Ottawa, Ontario K1H 8M5, Canada;
authors: Mir Munir A
authors: MM
authors: Rahim
authors: Department of Immunology, Sunnybrook Research Institute, University of Toronto, Toronto, Ontario M4N 3M5, Canada;
authors: David S J
authors: DS
authors: Allan
authors: Department of Immunology, Sunnybrook Research Institute, University of Toronto, Toronto, Ontario M4N 3M5, Canada;
authors: Jason H
authors: JH
authors: Fine
authors: Department of Immunology, Sunnybrook Research Institute, University of Toronto, Toronto, Ontario M4N 3M5, Canada;
authors: Christina L
authors: CL
authors: Kirkham
authors: Department of Immunology, Sunnybrook Research Institute, University of Toronto, Toronto, Ontario M4N 3M5, Canada;
authors: Jaehun
authors: J
authors: Ma
authors: Department of Immunology, Sunnybrook Research Institute, University of Toronto, Toronto, Ontario M4N 3M5, Canada;
authors: Miho
authors: M
authors: Tanaka
authors: Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, Ottawa, Ontario K1H 8M5, Canada;
authors: Megan M
authors: MM
authors: Tu
authors: Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, Ottawa, Ontario K1H 8M5, Canada;
authors: Andrew
authors: A
authors: Wight
authors: Prince Henry's Institute, Monash Medical Centre, Clayton, Victoria 3168, Australia; and.
authors: Vicky
authors: V
authors: Kartsogiannis
authors: Prince Henry's Institute, Monash Medical Centre, Clayton, Victoria 3168, Australia; and Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria 3168, Australia.
authors: Matthew T
authors: MT
authors: Gillespie
authors: Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, Ottawa, Ontario K1H 8M5, Canada; james.carlyle@utoronto.ca amakrigi@uottawa.ca.
authors: Andrew P
authors: AP
authors: Makrigiannis
authors: Department of Immunology, Sunnybrook Research Institute, University of Toronto, Toronto, Ontario M4N 3M5, Canada; james.carlyle@utoronto.ca amakrigi@uottawa.ca.
authors: James R
authors: JR
authors: Carlyle
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000276:immunology / Q000378:metabolism; D016026:Bone Marrow Transplantation / Q000379:methods*; D045744:Cell Line, Tumor; D005434:Flow Cytometry; D015870:Gene Expression / Q000276:immunology; D006084:Graft Rejection / Q000235:genetics / Q000276:immunology; D018380:Hematopoietic Stem Cell Transplantation / Q000379:methods; D064532:Histocompatibility Antigen H-2D / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism; D037181:Lectins, C-Type / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D023421:Models, Animal; D055651:NK Cell Lectin-Like Receptor Subfamily B / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014184:Transplantation, Homologous
chemical_list: D064532:Histocompatibility Antigen H-2D; C527212:Klrb1b protein, mouse; D037181:Lectins, C-Type; D008565:Membrane Proteins; D055651:NK Cell Lectin-Like Receptor Subfamily B; C429003:Ocil protein, mouse; D007371:Interferon-gamma