KIR3DS1-specific D0 domain polymorphisms disrupt KIR3DL1 surface expression and HLA binding

Tiernan J. Mulrooney, Aaron C. Zhang, Yehuda Goldgur, Jeanette E. Boudreau, Katharine C. Hsu

Research output: Contribution to journalArticlepeer-review

11 Scopus citations

Abstract

KIR3DL1 is a polymorphic inhibitory receptor that modulates NK cell activity through interacting with HLA-A and HLA-B alleles that carry the Bw4 epitope. Amino acid polymorphisms throughout KIR3DL1 impact receptor surface expression and affinity for HLA. KIR3DL1/S1 encodes inhibitory and activating alleles, but despite high homology with KIR3DL1, the activating receptor KIR3DS1 does not bind the same ligand. Allele KIR3DL1∗009 resulted from a gene recombination event between the inhibitory receptor allele KIR3DL1∗001 and the activating receptor allele KIR3DS1∗013. This study analyzed the functional impact of KIR3DS1-specific polymorphisms on KIR3DL1∗009 surface expression, binding to HLA, and functional capacity. Flowcytometric analysis of primary human NK cells as well as transfected HEK293T cells shows that KIR3DL1∗009 is expressed at a significantly lower surface density compared with KIR3DL1∗001. Using recombinant proteins of KIR3DL1∗001, KIR3DL1∗009, and KIR3DS1∗013 to analyze binding to HLA, we found that although KIR3DL1∗009 displayed some evidence of binding to HLA compared with KIR3DS1∗013, the binding was minimal compared with KIR3DL1∗001 and KIR3DL1∗005. Mutagenesis of polymorphic sites revealed that the surface phenotype and reduced binding of KIR3DL1∗009 are caused by the combined amino acid polymorphisms at positions 58 and 92 within the D0 extracellular domain. Resulting from these effects, KIR3DL1∗009+ NK cells exhibited significantly less inhibition by HLA-Bw4+ target cells compared with KIR3DL1∗001+ NK cells. The data from this study contribute novel insight into how KIR3DS1-specific polymorphisms in the extracellular region impact KIR3DL1 surface expression, ligand binding, and inhibitory function.

Original languageEnglish
Pages (from-to)1242-1250
Number of pages9
JournalJournal of Immunology
Volume195
Issue number3
DOIs
StatePublished - 1 Aug 2015
Externally publishedYes

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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