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,
* Department of Pediatrics and
Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY 10021; and
Immunology Program, Memorial Sloan-Kettering Cancer Center, Zuckerman Research Center, New York, NY 10021
The inhibitory 2DL1 and activating 2DS1 killer Ig-like receptors (KIR) both have shared ligand specificity for codon sequences in the C2 group HLA-Cw Ags. In this study, we have investigated NK cell activation by allogeneic target cells expressing different combinations of the HLA-KIR ligand groups C1, C2, and Bw4. We demonstrate that fresh NK cells as well as IL-2-propagated NK cells from 2DS1-positive donors that are homozygous for the C1 ligand group are activated in vitro by B lymphoblastoid cell lines expressing the C2 group. This response is, in part, due to the absence of C1 group recognition mediated by the inhibitory receptor 2DL2/3. This "missing self" alloresponse to C2, however, is rarely observed in NK cells from donors lacking 2DS1. Even in presence of 2DS1, the NK alloresponse is dramatically reduced in donors that have C2 group as "self." Analysis of selected NK clones that express 2DS1 mRNA and lack mRNA for 2DL1 demonstrates that activation by the C2 ligand and mAb cross-linking of 2DS1 in these clones induces IFN-
. Furthermore, this C2 group-induced activation is inhibited by Abs to both HLA class I and the receptor. Collectively, these studies demonstrate that NK cells from 2DS1-positive donors are activated by target cells that express the C2 group as an alloantigen. This leads to increased IFN--positive fresh NK cells and induces NK allocytotoxicity in IL2-propagated polyclonal NK cells and NK clones. This study also provides support for the concept that incompatibility for the HLA-KIR ligand groups C1, C2, and Bw4 dominates NK alloactivation in vitro.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by National Institutes of Health, National Institute of Allergy and Infectious Diseases Grant AI50193, National Cancer Institute Grants P01CA023766, CA08748, and T32 CA0941-28 (to J.H.C.), and the William H. Goodwin and Alice Goodman Fund and Commonwealth Cancer Foundation for Research/Experimental Therapeutics Center of Memorial Sloan–Kettering Cancer Center.
2 Address correspondence and reprint requests to Dr. Bo Dupont, Immunology Program, Memorial Sloan-Kettering Cancer Center, Zuckerman Research Center, Room Z1664, 1275 York Avenue, New York, NY 10021. E-mail address: dupontb{at}mskcc.org
3 Abbreviations used in this paper: LILR, leukocyte Ig-like receptor; BLCL, B lymphoblastoid cell line; HCT, hemopoietic stem cell transplantation; KIR, killer cell Ig-like receptor; SSP, sequence-specific primer; C1, HLA-KIR ligand group C1; C2, HLA-KIR ligand group C2; Bw4, HLA-KIR ligand group Bw4; KIR-A, KIR A haplotype; KIR-B, KIR B haplotype.
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