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

Natural killer (NK) cells are lymphocytes that have vital functions in innate and adaptive immunity, as well as placental reproduction. Polymorphic human leukocyte antigen (HLA) class I educates NK cells through interactions with killer cell immunoglobulin-like receptors (KIRs) and by supplying peptides that bind HLA-E to form ligands for CD94/NKG2A receptors on NK cells. HLA-B dimorphism in the leader peptide modulates this latter function: −21methionine (−21M) delivers functional peptides, but −21threonine (−21T) does not. Genetic analysis of human populations worldwide showed that haplotypes with −21M HLA-B rarely encoded 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 and the other preferentially supplying KIR ligands. This −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 demonstrated that M/M and M/T individuals have CD94/NKG2A⁺ NK cells that are better educated, phenotypically more diverse, and functionally more potent than those in T/T individuals. The KIR school of NK cell education evolved in the context of the much older CD94/NKG2A school, and this complementary coevolution may have facilitated the specialization of HLA haplotypes toward one school or the other.