KIR specificity and avidity of standard and unusual C1, C2, Bw4, Bw6 and A3/11 amino acid motifs at entire HLA:KIR interface between NK and target cells, the functional and evolutionary classification of HLA class I molecules

Abstract

Natural killer (NK) cells make vital contributions to the immune system and the reproductive system. Notably, NK cells of donor origin can recognize and kill residual leukaemic cells and cure malignant patients in hematopoietic stem cell (HSC) transplant setting. NK cell function is regulated by KIRs that recognize cognate HLA class I molecules on target cells, depending on their amino acid residues. In review, we addressed the question of binding capacity and avidity of HLA class I molecules to different killer cell immunoglobulin‐like receptors (KIRs) depending on all interacting amino acid residues both on HLA and KIR side. We searched PubMed database and analysed available HLA:KIR crystallographic data for amino acid residues in HLA molecules, those physically involved in binding KIRs (termed here the “entire KIR interface”). Within entire KIR interface, we selected five functional sequence motifs (14–19, 66–76, 77–84, 88–92 and 142–151) and classified them according to the conservation of their amino acid sequences among 8,942 HLA class I molecules. Although some conserved amino acid motifs were shared by different groups of KIR ligands, the HLA motif combinations were exclusive for the ligand groups. In 135 common HLA class I molecules with known HLA:KIR recognition, we found 54 combinations of five motifs in each of the KIR‐binding interfaces (C1, C2, Bw4, A3/11) and conserved non‐KIR‐binding interfaces. Based on the entire KIR interface, this analysis allowed to classify 8,942 HLA class I molecules into KIR specificity groups. This functional and evolutionary classification of entire KIR interfaces provides a tool for unambiguously predicting HLA:KIR interactions for common and those HLA molecules that have not yet been functionally tested. Considering the entire KIR interface in HLA class I molecules, functional interactions of HLA and KIR can be predicted in immune responses, reproduction and allotransplantation. Further functional studies are needed on the HLA:KIR interaction variations caused by the repertoires of peptides presented by HLA molecules and KIR polymorphisms at allelic level.

Allograft recognition by recipient's natural killer cells: Molecular mechanisms and role in transplant rejection

“…Similar observations were made for HLA‐A and ‐B Bw4 positive molecules 57,58 . On top of these amino acid substitutions on HLA class I ligands, polymorphisms at the allelic level in inhibitory KIRs may also modify their binding affinity to cognate HLA class I ligands 55 . In line with these data, another convincing hypothesis to explain that some patients with a genetically‐predicted missing self do not develop rejection lesions is that their NK cells are not correctly educated because of a low avidity of the inhibitory KIR/HLA class I interaction during NK cell education process.…”

“…Since the 2000s, it has been highlighted that amino acid residues located in other positions can modulate the specificity and avidity of inhibitory KIRs and HLA class I molecules interactions 55 . For instance, the substitution of an alanine by a threonine in position 73 is associated with an increased C2‐KIR2DL1 and C1‐KIR2DL2–3 avidity 55,56 . Similar observations were made for HLA‐A and ‐B Bw4 positive molecules 57,58 .…”

“…For a long time, the interactions between inhibitory KIRs and their ligands were thought to rely only on amino acid residues located in positions 77 and 80 of HLA class I molecules 52–54 . Since the 2000s, it has been highlighted that amino acid residues located in other positions can modulate the specificity and avidity of inhibitory KIRs and HLA class I molecules interactions 55 . For instance, the substitution of an alanine by a threonine in position 73 is associated with an increased C2‐KIR2DL1 and C1‐KIR2DL2–3 avidity 55,56 .…”

The Adverse Impact of Tumor Microenvironment on NK-Cell

“…Inhibitory receptors include C-type lectin receptors (CD94/NKG2A/B) and KIRs (KIR-2DL and KIR-3DL). MHC class I (MHC-I) molecules are present on most cells, and NK cell inhibitory receptors (KIRs and CD94/ NKG2A/B) can bind to them to prevent NK cell-mediated killing (13)(14)(15)(16)(17); however, when stressed cells downregulated MHC-I expression, NK cells are activated through "missing-self recognition" by losing their inhibitory signals. When cancer cells show elevated level of NK cell receptor, like NKG2D in response to stress, "self-induced" activation mechanism occur and leading the engagement of NK cells.…”

Characterization of the novel KIR3DL2 allele, KIR3DL2*113

“…Human killer cell immunoglobulin‐like receptors (KIRs) are a subfamily of the immunoglobulin superfamily. The KIRs interact with their ligands (HLA class I molecules) to affect the function of Natural killer (NK) cells, and play an important role in health and disease, including the successful outcome of hematopoietic stem cell transplantation, infection disease and certain tumors . The KIRs have been shown to be highly polymorphic with different expression profiles, abundant alleles and variation of the gene copy number .…”