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

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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. 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.

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