Class I HLA haplotypes form two schools that educate NK cells in different ways

Abstract

Summary 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.

Differential contribution of education through KIR2DL1, KIR2DL3, and KIR3DL1 to antibody-dependent (AD) NK cell activation and ADCC

“…NKG2A + cells are educated through interactions with HLA‐E, both of which exhibit limited variation and are expressed in most individuals . It is important to note that education through NKG2A may differ from one person to another based on whether the HLA haplotype of the subject favors delivery of MHC‐I signal sequence nonamer epitopes to ligands for NKG2A versus iKIR . We did not detect a difference in the %GzB + CEM cells generated in our ADCC‐GTL experimental set up by SPNKG2A + NK cells based on the T/M amino acid dimorphism at position ‐21 of the HLA signal sequence of the HLA‐B alleles expressed by the donors whose cells were used in these experiments (not shown).…”

The Broad Spectrum of Human Natural Killer Cell Diversity

“…Notably, the availability of KIR-specific MHC class IA ligands is dependent on the HLA haplotype of the individual, because different HLA molecules contain different KIR-binding epitopes. Therefore, different KIR + NK cells are educated in different individuals (Horowitz et al, 2016), and this directly impacts whether or not NK cell alloreactivity exists in the setting of haploidentical allo-HSCT for AML (Velardi et al, 2012). …”

Missing or altered self: human NK cell receptors that recognize HLA-C

“…This combines conserved receptors that recognize non-polymorphic MHC class I with diverse receptors that recognize polymorphic MHC class I (Guethlein et al 2015). In humans, HLA-E binds a restricted set of peptides, which are largely derived from the leader sequences of the polymorphic HLA class I molecules, and thus forms the ligand for CD94:NKG2 lectin-like receptors (Braud et al 1998; Horowitz et al 2016). Because both receptor and ligand are genetically conserved, these interactions are a constant feature of human immune responses.…”