title: Class I HLA haplotypes form two schools that educate NK cells in different ways.
abstract: Natural killer (NK) cells are lymphocytes having vital functions in innate and adaptive immunity, as well as placental reproduction. Controlling education and functional activity of human NK cells are various receptors that recognize HLA class I on the surface of tissue cells. Epitopes of polymorphic HLA-A,-B and -C are recognized by equally diverse killer cell immunoglobulin-like receptors (KIR). In addition, a peptide cleaved from the leader sequence of HLA-A,-B or -C must bind to HLA-E for it to become a ligand for the conserved CD94:NKG2A receptor. Methionine/threonine dimorphism at position -21 of the leader sequence divides HLA-B allotypes into a majority having -21T that do not supply HLA-E binding peptides and a minority having -21M, that do. Genetic analysis of human populations worldwide shows how haplotypes with -21M HLA-B rarely encode the KIR ligands: Bw4+HLA-B and C2+HLA-C KIR. Thus there are two fundamental forms of HLA haplotype: one preferentially supplying CD94:NKG2A ligands, the other preferentially supplying KIR ligands. -21 HLA-B dimorphism divides the human population into three groups: M/M, M/T and T/T. Mass cytometry and assays of immune function, shows how M/M and M/T individuals have CD94:NKG2A+NK cells which are better educated, phenotypically more diverse and functionally more potent than those in T/T individuals. Fundamental new insights are given to genetic control of NK cell immunity and the evolution that has limited the number of NK cell receptor ligands encoded by an HLA haplotype. These finding suggest new ways to dissect the numerous clinical associations with HLA class I.
authors.affiliation: Departments of Structural Biology and Microbiology & Immunology, Stanford University School of Medicine, Stanford, CA, 94305, USA; Stanford Immunology, Stanford University School of Medicine, Stanford, CA, 94305, USA.
authors.forename: Amir
authors.initials: A
authors.lastname: Horowitz
authors.affiliation: Departments of Structural Biology and Microbiology & Immunology, Stanford University School of Medicine, Stanford, CA, 94305, USA; Stanford Immunology, Stanford University School of Medicine, Stanford, CA, 94305, USA.
authors.forename: Zakia
authors.initials: Z
authors.lastname: Djaoud
authors.affiliation: Departments of Structural Biology and Microbiology & Immunology, Stanford University School of Medicine, Stanford, CA, 94305, USA; Stanford Immunology, Stanford University School of Medicine, Stanford, CA, 94305, USA.
authors.forename: Neda
authors.initials: N
authors.lastname: Nemat-Gorgani
authors.affiliation: Departments of Structural Biology and Microbiology & Immunology, Stanford University School of Medicine, Stanford, CA, 94305, USA; Stanford Immunology, Stanford University School of Medicine, Stanford, CA, 94305, USA.
authors.forename: Jeroen
authors.initials: J
authors.lastname: Blokhuis
authors.affiliation: Departments of Structural Biology and Microbiology & Immunology, Stanford University School of Medicine, Stanford, CA, 94305, USA; Stanford Immunology, Stanford University School of Medicine, Stanford, CA, 94305, USA.
authors.forename: Hugo G
authors.initials: HG
authors.lastname: Hilton
authors.affiliation: Center for Infectious Medicine, Department of Medicine, Karolinska Institute, Stockholm, Sweden; Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Paris, France.
authors.forename: Vivien
authors.initials: V
authors.lastname: Béziat
authors.affiliation: Center for Infectious Medicine, Department of Medicine, Karolinska Institute, Stockholm, Sweden; Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital, 0310 Oslo, Norway.
authors.forename: Karl-Johan
authors.initials: KJ
authors.lastname: Malmberg
authors.affiliation: Departments of Structural Biology and Microbiology & Immunology, Stanford University School of Medicine, Stanford, CA, 94305, USA; Stanford Immunology, Stanford University School of Medicine, Stanford, CA, 94305, USA.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Norman
authors.affiliation: Departments of Structural Biology and Microbiology & Immunology, Stanford University School of Medicine, Stanford, CA, 94305, USA; Stanford Immunology, Stanford University School of Medicine, Stanford, CA, 94305, USA.
authors.forename: Lisbeth A
authors.initials: LA
authors.lastname: Guethlein
authors.affiliation: Departments of Structural Biology and Microbiology & Immunology, Stanford University School of Medicine, Stanford, CA, 94305, USA; Stanford Immunology, Stanford University School of Medicine, Stanford, CA, 94305, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Parham