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Hierarchy of the Human Natural Killer Cell Response Is Determined by Class and Quantity of Inhibitory Receptors for Self-HLA-B and HLA-C Ligands¹

Junli Yu^*, Glenn Heller, Joseph Chewning, Sungjin Kim^¶, Wayne M. Yokoyama^¶ and Katharine C. Hsu^2,

^* Immunology Program, Department of Epidemiology and Biostatistics, Department of Pediatrics, and Department of Medicine, Sloan-Kettering Cancer Center, New York, NY 10021; and ^¶ Howard Hughes Medical Institute, Department of Medicine, Washington University, St. Louis, MO 63110

The interaction of NK inhibitory killer Ig-like receptors (KIRs) with self-MHC class I molecules mediates NK tolerance to self while conferring functional competence. Through single-cell analysis of intracellular IFN- production and NK clone cytotoxicity we evaluated the resting NK repertoire, analyzing the responsiveness of NK subgroups expressing discrete combinations of non-KIR and KIR class I-specific receptors. CD94:NKG2A and Ig-like transcript 2 (ILT2)-expressing cells have a modest response to class I-negative target cells, but NK cells expressing inhibitory KIRs to self-MHC class I ligands, both HLA-B and HLA-C ligands, achieve significantly higher effector capacity. There is a dose effect of KIR for self-MHC on effector capacity, but even in the most highly responsive NK cells expressing more than one inhibitory KIR for self-MHC the presentation of only one cognate MHC ligand is sufficient to abolish response. Among KIR⁺ cells there is preferential expression for inhibitory KIR for self-MHC. The likelihood of KIR expression is influenced by whether other KIRs are already expressed on the same cell, supporting a model of serial acquisition of KIR expression. These findings define how inhibitory receptor and autologous HLA interactions impact single-cell function and demonstrate that the resting human NK repertoire is highly attuned but variegated in response. These findings have important implications for the resting NK response to viral pathogens and malignancy, for donor selection in allogeneic hemopoietic cell transplantation, and for models of NK tolerance.

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 in part by Marrow Foundation Grant 1K04-01 (to K.C.H.) and National Institutes of Health Grant HL070053 (to K.C.H.).

² Address correspondence and reprint requests to Dr. Katharine C. Hsu, Adult Allogeneic Bone Marrow Transplantation Service, Department of Medicine, Box 336, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021. E-mail address: hsuk{at}mskcc.org

³ Abbreviations used in this paper: ILT2, Ig-like transcript 2; AHSCT, allogeneic hemopoietic stem cell transplantation; BLCL, B lymphoblastoid cell line; KIR, killer Ig-like receptor; NS-KIR, inhibitory KIR expressed by NK cells for nonself-MHC class I; S-KIR, inhibitory KIR expressed by NK cells for self-MHC class I.

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The JI 2007 179: 5615-5616. [Full Text]  

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