KIR2DS4 is a product of gene conversion with KIR3DL2 that introduced specificity for HLA-A*11 while diminishing avidity for HLA-C

Thorsten Graef, Achim K. Moesta, Paul J. Norman, Laurent Abi-Rached, Luca Vago, Anastazia M. Older Aguilar, Michael Gleimer, John A. Hammond, Lisbeth A. Guethlein, David A. Bushnell, Philip J. Robinson, Peter Parham

Research output: Contribution to journalArticlepeer-review

Abstract

Human killer cell immunoglobulin-like receptors (KIRs) are distinguished by expansion of activating KIR2DS, whose ligands and functions remain poorly understood. The oldest, most prevalent KIR2DS is KIR2DS4, which is represented by a variable balance between "fulllength" and "deleted" forms. We find that full-length 2DS4 is a human histocompatibility leukocyte antigen (HLA) class I receptor that binds specifically to subsets of C1 + and C2+ HLA-C and to HLA-A*11, whereas deleted 2DS4 is nonfunctional. Activation of 2DS4+ NKL cells was achieved with A*1102 as ligand, which differs from A*1101 by unique substitution of lysine 19 for glutamate, but not with A*1101 or HLA-C. Distinguishing KIR2DS4 from other KIR2DS is the proline-valine motif at positions 71-72, which is shared with KIR3DL2 and was introduced by gene conversion before separation of the human and chimpanzee lineages. Site-directed swap mutagenesis shows that these two residues are largely responsible for the unique HLA class I specificity of KIR2DS4. Determination of the crystallographic structure of KIR2DS4 shows two major differences from KIR2DL: displacement of contact loop L2 and altered bonding potential because of the substitutions at positions 71 and 72. Correlation between the worldwide distributions of functional KIR2DS4 and HLA-A*11 points to the physiological importance of their mutual interaction.

Original languageEnglish
Pages (from-to)2557-2572
Number of pages16
JournalJournal of Experimental Medicine
Volume206
Issue number11
DOIs
Publication statusPublished - Oct 26 2009

ASJC Scopus subject areas

  • Immunology
  • Immunology and Allergy
  • Medicine(all)

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