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Malcolm John Wyness Sim, Stacy A Malaker, Ayesha Khan, Janet M Stowell, Jeffrey Shabanowitz, Mary E Peterson, Sumati Rajagopalan, Donald F Hunt, Daniel M Altmann, Eric O Long, Rosemary J Boyton, Canonical and cross-reactive binding of NK cell inhibitory receptors to HLA-C allotypes is dictated by peptides bound to HLA-C, The Journal of Immunology, Volume 198, Issue Supplement_1, May 2017, Page 222.25, https://doi.org/10.4049/jimmunol.198.Supp.222.25
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Abstract
Human NK cell activity is regulated by killer-cell Ig-like receptors (KIR) that bind HLA class I. Combinations of KIR and HLA genotypes are associated with disease, including susceptibility to viral infection and disorders of pregnancy. KIR2DL1 binds group C2 HLA-C (Lys80), while KIR2DL2/3 bind group C1 HLA-C (Asn80). The goal of this study was to determine how the endogenous HLA-C peptide repertoire influences specific binding of inhibitory KIR to HLA-C allotypes.
HLA-C*05:01 (C2) and HLA-C*08:02 (C1) have identical sequences apart from the key KIR specificity determining residues at 77 and 80. Endogenous peptides were eluted from HLA-C*05:01 and used to test KIR2DL1 and KIR2DL2/3 binding to HLA-C*05:01 and HLA-C*08:02 and subsequent impact on NK cell function. Canonical binding of KIR2DL1 to C2 occurred with the majority of peptides tested, while KIR2DL2/3 binding to C1 occurred with a subset of peptides. Cross-reactive binding of KIR2DL2/3 with C2 was restricted to even fewer peptides. Unexpectedly, two peptides promoted binding of the C2 specific KIR2DL1 to the C1 allotype.
KIR2DL2/3 binding to C1 is more peptide selective than KIR2DL1 binding to C2, providing an explanation for why KIR2DL3–C1 interactions appear weaker than KIR2DL1–C2. Cross-reactive KIR binding is characterized by even higher peptide selectivity. These differences in peptide selectivity may aid the interpretation of human disease associations with KIR and HLA, while peptide sequence-driven KIR binding provides a potential mechanism for pathogen or self-peptide to modulate KIR binding and NK cell activation.
