title: Molecular basis for LLT1 protein recognition by human CD161 protein (NKRP1A/KLRB1).
abstract: Human Th17 cells express high levels of CD161, a member of the killer cell lectin-like receptor (KLR) family (also referred to as NK receptor-P1A (NKRP1A) or KLRB1), as a representative marker. CD161 is also expressed on natural killer (NK) cells and NKT cells. Lectin-like transcript 1 (LLT1), another KLR family member, was recently identified as a ligand for CD161. This interaction may play pivotal roles in the immunomodulatory functions of Th17 cells as well as those of NK and NKT cells. However, the molecular basis for the interaction is poorly understood. Here we show that the extracellular domain of CD161 bound directly to LLT1 with a K(d) of 48 μM and with the fast kinetics typical of cell-cell recognition receptors. Mutagenesis revealed that the similar membrane-distal β-sheet and loop regions of both CD161 and LLT1 were utilized for the binding, and notably, these regions correspond to the ligand-binding sites for major histocompatibility complex (MHC)-recognizing KLRs. Furthermore, we found a pair of detrimental mutations for both molecules that restored the binding. These results reveal a new template model for the recognition mode between the KLR family members and provide insights into the molecular mechanism underlying Th17/NK/NKT-mediated immune responses.
authors.affiliation: Laboratory of Biomolecular Science, Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo 060-0812, Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Kamishikiryo
authors.forename: Hideo
authors.initials: H
authors.lastname: Fukuhara
authors.forename: Yuki
authors.initials: Y
authors.lastname: Okabe
authors.forename: Kimiko
authors.initials: K
authors.lastname: Kuroki
authors.forename: Katsumi
authors.initials: K
authors.lastname: Maenaka
mesh_terms: D057809:HEK293 Cells; D006649:Histocompatibility Antigens / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007694:Killer Cells, Natural / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D037181:Lectins, C-Type / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D009154:Mutation; D055651:NK Cell Lectin-Like Receptor Subfamily B / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D055611:Natural Killer T-Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D011956:Receptors, Cell Surface / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D058504:Th17 Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism
chemical_list: C400041:CLEC2D protein, human; D006649:Histocompatibility Antigens; C527203:KLRB1 protein, human; D037181:Lectins, C-Type; D055651:NK Cell Lectin-Like Receptor Subfamily B; D011956:Receptors, Cell Surface