Coevolution of Killer Cell Ig-Like Receptors with HLA-C To Become the Major Variable Regulators of Human NK Cells

Abstract

Interactions between HLA class I and killer cell immunoglobulin-like receptors (KIR) diversify human NK cell responses. Dominant KIR ligands are the C1 and C2 epitopes of MHC-C, a young locus restricted to humans and great apes. C1 and C1-specific KIR evolved first, being present in orangutan and functionally like their human counterparts. Orangutans lack C2 and C2-specific KIR, but have a unique C1+C2 specific KIR that binds equally to C1 and C2. Such a receptor was likely the mechanism by which C2-KIR interaction evolved from C1-KIR while avoiding a non-functional intermediate: either orphan receptor or ligand. Orangutan inhibitory MHC-C reactive KIR pair with activating receptors of identical avidity and specificity, contrasting with the selective attenuation of human activating KIR. The orangutan C1-specific KIR reacts or cross-reacts with all four polymorphic epitopes (C1, C2, Bw4, and A3/11) recognized by human KIR, revealing their structural commonality. Saturation mutagenesis at specificity-determining position 44, demonstrates that KIR are inherently restricted to binding just these four epitopes, either individually or in combination. This restriction frees the majority of HLA-A and –B variants to be dedicated T-cell receptor ligands, not subject to conflicting pressures from the NK cell and T cell arms of the immune response.

An improved method for HLA-B and -C supratyping

“…Amongst the inhibitory receptors, KIR2DL2 and KIR2DL3 bind to the ancient HLA-C alleles of group-1 (C1) that share the N80 residue (HLA-C*01, *03, *07, *08 and some other alleles) . On the other hand, KIR2DL1 recognizes the more recently evolved group of alleles sharing the C2-epitope characterized by K80 Older Aguilar et al, 2010) (the majority of HLA-C*04, -C*05, -C*06 and some other alleles). KIR2DL2 is apparently less specific than previously believed, since it recognizes also some HLA-C alleles characterized by the C2-epitope (Hilton et al, 2012;Moesta and Parham, 2012).…”

Major Histocompatibility Complex Class-I-Interacting Natural Killer Cell Receptors of Nonhuman Primates

“…Gorilla lineage III KIR2D can also bind to MHC-C1 and MHC-C2 types. In contrast, all orangutan MHC-C allotypes are of the MHC-C1 type [29] , and consequently, orangutan KIR2D molecules have only specificity for MHC-C1. An exception is orangutan KIR2DLB, which is specifically interacting with both HLA-C1 and HLA-C2 types.…”

“…An exception is orangutan KIR2DLB, which is specifically interacting with both HLA-C1 and HLA-C2 types. This receptor is seen as an evolutionary intermediate in the development of MHC-C1-and MHC-C2-specific lineage III KIRs in other hominid primates [29] . Notably, the MHC-C gene is not fixed in orangutan populations, with 25% of individuals being negative for this gene [25] .…”

“…Human, chimpanzee and orangutan KIR molecules specifically interact with MHC class I molecules of the MHC-A, MHC-B and MHC-C types [7,29] . In humans, these encompass KIR2DL1 (interacting with HLA-C2 types), KIR2DS1 (HLA-C2), KIR2DL2/3 (HLA-C1 and certain HLA-C2), KIR2DL4 (HLA-G), KIR2DS4 (certain HLA-C1 and HLA-C2, HLA-A * 11), KIR3DL1 (Bw4 epitope-carrying HLA class I) and KIR3DL2 (HLA-A * 003, HLA-A * 011).…”

Killer Immunoglobulin-Like Receptors and Their Ligands

“…It is known that MHC-C evolved only recently in humans and great apes (at least in orangutans), and not before. Apparently, the KIR and C1 loci evolved before the KIR-C2 since in Orangutans neither MHC-C2 alleles nor C2-specific KIRs could be detected (Older Aguilar et al, 2010). KIR3DL1 loci encode specific receptors for HLA-B alleles that share the public epitope Bw4 corresponding to amino acids 77-83 on the HLA class I 1-helix with the exception of HLA-B*13:01 and HLA-B*13:02 (Foley et al, 2008), and for some HLA-A alleles characterized by Bw4-supertypic specificity like A23, A24, , and A32 (Stern et al, 2008;Thananchai et al, 2007).…”