title: Differential but competitive binding of Nogo protein and class i major histocompatibility complex (MHCI) to the PIR-B ectodomain provides an inhibition of cells.
abstract: Binding of class I MHC molecules (MHCI) to an inhibitory receptor, PIR-B, expressed on B cells and myeloid cells provides constitutive cellular inhibition, thus ensuring peripheral tolerance. Recent unexpected findings pointed to a novel inhibitory role of PIR-B in neurite regeneration through binding to three axonal outgrowth inhibitors of myelin, including Nogo. Thus, it becomes interesting to determine whether the actions of the inhibitory myelin proteins and MHCI could coexist independently or be mutually exclusive as to the PIR-B-mediated immune and neural cell inhibition. Here, we present data supporting the competition of Nogo- and MHCI-mediated inhibition where they coexist. Kinetic analyses of Nogo and MHCI binding to the whole or a part of the recombinant PIR-B ectodomain revealed that PIR-B binds with higher affinity to Nogo than MHCI and that the MHCI binding only occurred with the N-terminal domains of PIR-B, whereas Nogo binding occurred with either the N- or C-terminal ectodomains. Importantly, kinetic tests indicated that the binding to PIR-B of Nogo and MHCI was competitive. Both endogenous and exogenous Nogo intensified the PIR-B-mediated suppression of interleukin-6 release from lipopolysaccharide-stimulated wild-type, but not PIR-B-deficient, cultured mast cells, indicating that PIR-B mediates Nogo-induced inhibition. Thus, we propose a novel mechanism by which PIR-B-mediated regulation is achieved differentially but competitively via MHCI and Nogo in cells of the immune system.
authors.affiliation: Department of Experimental Immunology, Institute of Development, Aging and Cancer, Tohoku University, Sendai 980-8575, Japan.
authors.forename: Haruka
authors.initials: H
authors.lastname: Matsushita
authors.forename: Shota
authors.initials: S
authors.lastname: Endo
authors.forename: Eiji
authors.initials: E
authors.lastname: Kobayashi
authors.forename: Yuzuru
authors.initials: Y
authors.lastname: Sakamoto
authors.forename: Keisuke
authors.initials: K
authors.lastname: Kobayashi
authors.forename: Kohji
authors.initials: K
authors.lastname: Kitaguchi
authors.forename: Kimiko
authors.initials: K
authors.lastname: Kuroki
authors.forename: Arvid
authors.initials: A
authors.lastname: Söderhäll
authors.forename: Katsumi
authors.initials: K
authors.lastname: Maenaka
authors.forename: Akira
authors.initials: A
authors.lastname: Nakamura
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Strittmatter
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Takai
mesh_terms: D000818:Animals; D001667:Binding, Competitive; D005260:Female; D006680:HLA Antigens / Q000378:metabolism; D059951:HLA-G Antigens; D015395:Histocompatibility Antigens Class I / Q000378:metabolism*; D006801:Humans; D007155:Immunologic Factors / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008407:Mast Cells / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009185:Myelin Proteins / Q000378:metabolism*; D018992:Myelin-Associated Glycoprotein / Q000378:metabolism; D018377:Neurotransmitter Agents / Q000378:metabolism; D000070798:Nogo Proteins; D017434:Protein Structure, Tertiary; D051381:Rats; D011971:Receptors, Immunologic / Q000737:chemistry* / Q000378:metabolism*; D013379:Substrate Specificity; D001613:beta 2-Microglobulin / Q000378:metabolism
chemical_list: D006680:HLA Antigens; D059951:HLA-G Antigens; D015395:Histocompatibility Antigens Class I; D007155:Immunologic Factors; D015850:Interleukin-6; D008070:Lipopolysaccharides; D009185:Myelin Proteins; D018992:Myelin-Associated Glycoprotein; D018377:Neurotransmitter Agents; D000070798:Nogo Proteins; C105948:Pira1 protein, mouse; C105949:Pirb protein, mouse; C000603199:RTN4 protein, human; D011971:Receptors, Immunologic; C000603201:Rtn4 protein, mouse; C000603197:Rtn4 protein, rat; D001613:beta 2-Microglobulin