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* Department of Structural Biology and Department of Microbiology and Immunology, School of Medicine and
Interdisciplinary Program in Immunology, Stanford University, Stanford, CA 94305
Interactions between HLA-C ligands and inhibitory killer cell Ig-like receptors (KIR) control the development and response of human NK cells. This regulatory mechanism is usually described by mutually exclusive interactions of KIR2DL1 with C2 having lysine 80, and KIR2DL2/3 with C1 having asparagine 80. Consistent with this simple rule, we found from functional analysis and binding assays to 93 HLA-A, HLA-B, and HLA-C isoforms that KIR2DL1*003 bound all C2, and only C2, allotypes. The allotypically related KIR2DL2*001 and KIR2DL3*001 interacted with all C1, but they violated the simple rule through interactions with several C2 allotypes, notably Cw*0501 and Cw*0202, and two HLA-B allotypes (B*4601 and B*7301) that share polymorphisms with HLA-C. Although the specificities of the "cross-reactions" were similar for KIR2DL2*001 and KIR2DL3*001, they were stronger for KIR2DL2*001, as were the reactions with C1. Mutagenesis explored the avidity difference between KIR2DL2*001 and KIR2DL3*001. Recombinant mutants mapped the difference to the Ig-like domains, where site-directed mutagenesis showed that the combination, but not the individual substitutions, of arginine for proline 16 in D1 and cysteine for arginine 148 in D2 made KIR2DL2*001 a stronger receptor than KIR2DL3*001. Neither residue 16 or 148 is part of, or near to, the ligand-binding site. Instead, their juxtaposition near the flexible hinge between D1 and D2 suggests that their polymorphisms affect the ligand-binding site by changing the hinge angle and the relative orientation of the two domains. This study demonstrates how allelic polymorphism at sites distal to the ligand-binding site of KIR2DL2/3 has diversified this receptor’s interactions with HLA-C.
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1 This work was supported by National Institutes of Health Grant AI022039 (to P.P.), Stanford Graduate Fellowships (to A.K.M. and M.G.), a National Science Foundation Graduate Fellowship (to A.K.M.), a Howard Hughes Medical Institute Pre-doctoral Fellowship (to M.G.), and a Lymphoma Research Foundation Fellowship (to P.J.N.).
2 Address correspondence and reprint requests to Dr. Peter Parham, Department of Structural Biology, Stanford University, Fairchild D-159, 299 Campus Drive West, Stanford, CA 94305. E-mail address: peropa{at}stanford.edu
3 Abbreviations used in this paper: KIR, killer cell Ig-like receptor; NKL, a leukemia-derived cell line with NK cell-like properties; SSP-PCR, sequence-specific polymorphism-PCR.
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  A. M. Sharkey, L. Gardner, S. Hiby, L. Farrell, R. Apps, L. Masters, J. Goodridge, L. Lathbury, C. A. Stewart, S. Verma, et al. Killer Ig-Like Receptor Expression in Uterine NK Cells Is Biased toward Recognition of HLA-C and Alters with Gestational Age J. Immunol., July 1, 2008; 181(1): 39 - 46. [Abstract] [Full Text] [PDF]
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