The Journal of Experimental Medicine
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Published 7 October 2002. doi:10.1084/jem.20020304
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© Rockefeller University Press, 0022-1007/2002/10/911/ $5.00
The Journal of Experimental Medicine, Volume 196, Number 7, October 7, 2002 911-921
The D0 Domain of KIR3D Acts as a Major Histocompatibility Complex Class I Binding Enhancer

Salim I. Khakoo, Ron Geller, Sunny Shin, Jomaquai A. Jenkins and Peter Parham

Department of Structural Biology, and Department of Microbiology and Immunology, Stanford University School of Medicine, Sherman Fairchild Building, Stanford, CA 94305

Address correspondence to Dr. Peter Parham, Department of Structural Biology, Sherman Fairchild Building, 299 Campus Dr. West, Stanford University School of Medicine, Stanford, CA 94305-5126. Phone: 650-723-7456; Fax: 650-723-8464; E-mail: peropa{at}leland.stanford.edu

In contrast to the KIR2D:HLA-C interaction, little is known of KIR3DL1's interaction with HLA-B or the role of D0, the domain not present in KIR2D. Differences in the strength and specificity for major histocompatibility complex class I of KIR3DL1 and its common chimpanzee homologue Pt-KIR3DL1/2 were exploited to address these questions. Domain-swap, deletion, and site-directed mutants of KIR3DL1 were analyzed for HLA-B binding using a novel, positively signaling cell–cell binding assay. Natural ‘deletion’ of residues 50 and 51 from its D0 domain causes Pt-KIR3DL1/2 to bind Bw4+ HLA-B allotypes more avidly than does KIR3DL1. Deletion of these residues from KIR3DL1, or their substitution for alanine, enhanced binding of Bw4+ HLA-B. None of 15 different point mutations in D0 abrogated KIR3DL1 binding to Bw4+ HLA-B. In contrast point mutations in the D1 and D2 domains of KIR3DL1, made from knowledge of KIR2D:HLA-C interactions, disrupted binding to Bw4+ HLA-B. The results are consistent with a model in which D1 and D2 make the principal contacts between KIR3DL1 and HLA-B while D0 acts through a different mechanism to enhance the interaction. This modulatory role for D0 is compatible with natural loss of expression of the D0 domain, a repeated event in the evolution of functional KIR genes.

Key Words: natural killer cells • killer cell immunoglobulin-like receptors • MHC class I • human • chimpanzee


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