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Killer Ig-Like Receptor Ligand Mismatch Directs NK Cell Expansion In Vitro

Mingus J. J. Rose^*,, Andrew G. Brooks^*, Lisbeth A. Stewart, Thi H. Nguyen^, and Anthony P. Schwarer^1,,

^* Department of Microbiology and Immunology, University of Melbourne, Melbourne, Australia; Malignant Haematology and Stem Cell Transplantation Service, Alfred Hospital, Melbourne, Australia; and Department of Immunology, Monash University, Melbourne, Australia

NK cell alloreactivity is governed largely through failure to detect self-HLA class I ligands by the clonally distributed inhibitory killer Ig-like receptors (KIR) expressed on the NK cell surface. In this study, we investigated the extent to which HLA class I-KIR interactions influence human NK cell proliferation in the allogeneic setting. NK cells were cultured with feeder cells either matched or mismatched for inhibitory KIR ligands, the latter lacking one or more ligands present in the NK cell donor. In postculture cytotoxicity assays, the ability of polyclonal NK cells to kill KIR ligand-mismatched targets was enhanced by exposure to appropriately mismatched feeder cells in prior culture. This corresponded with an increased frequency of postculture donor NK cells expressing a given inhibitory KIR if the allogeneic feeder cells used in the culture lacked its ligand. Similar skewing of KIR distribution was seen in clonally expanded NK cells. Finally, a flow cytometry-based proliferation assay was used to show KIR-specific NK cell division in response to missing self. The findings demonstrate that KIR distribution among a population of alloresponding peripheral blood NK cells is shaped by the HLA class I environment.

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 Address correspondence and reprint requests to Assoc. Prof. Anthony P. Schwarer, Malignant Haematology and Stem Cell Transplantation Service, 1st Floor, South Block, WBRC, Alfred Hospital, Melbourne, Victoria 3004, Australia. E-mail address: a.schwarer{at}alfred.org.au

² Abbreviations used in this paper: KIR, killer Ig-like receptor; allo-HSCT, allogeneic hematopoietic stem cell transplantation.