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* Center for Infectious Medicine, Department of Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden; and
Division of Clinical Immunology, Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden
Stem cell transplantation across HLA barriers may trigger NK cell-mediated graft-vs-leukemia effects leading to improved survival for patients with hematological malignancies. However, the genetic algorithm based on killer cell Ig-like receptor (KIR) and HLA genes used to predict NK cell alloreactivity have yielded discrepant results. Accordingly, it has been difficult to define transplantation settings that favor NK cell alloreactivity. In this study, we have used multiparameter flow cytometry to simultaneously analyze the cell surface expression of all four major inhibitory KIR and CD94/NKG2A to determine the size of the alloreactive NK cell repertoires in 31 individuals homozygous for the group A KIR haplotype. We observed a vast variability in the frequencies of cells with an alloreactive potential, ranging from 0 to 62% of the total NK cell population depending on which, and how many, KIR ligands were missing in theoretical recipients. This analysis required a functional examination of KIR3DL2-single positive NK cells, showing that this subset was hyporesponsive in individuals harboring the cognate ligands HLA-A3/A11. The results provide new insights into the variability of the functional alloreactive NK cell repertoire and have implications for donor selection in hematopoietic stem cell transplantation and adoptive NK cell-based immunotherapy.
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 grants from the Swedish Foundation for Strategic Research, the Swedish Research Council, the Swedish Cancer Society, the Swedish Children’s Cancer Foundation, the Cancer Society of Stockholm, the Royal Swedish Academy of Sciences, the Tobias Foundation, the Söderberg foundation, and the Karolinska Institutet.
C.F. designed the study, performed experiments, data analysis, and interpretation, and wrote the paper; S.A. performed experiments, data analysis, and interpretation, and wrote the paper; A.B. performed experiments and data analysis; M.C. contributed to donor collection, KIR genotyping, and manuscript preparation; M.S. performed HLA genotyping; N.K.B. and J.M. contributed to experimental design and manuscript preparation; B.C.B. contributed to donor collection and KIR genotyping; H.-G.L. performed data interpretation and manuscript preparation; and K.-J.M. designed the study, performed data analysis and interpretation, and wrote the paper.
2 C.F. and S.A. contributed equally to this work.
3 Address correspondence and reprint requests to Dr. Karl-Johan Malmberg, Center for Infectious Medicine, F59, Department of Medicine, Karolinska Institutet, Karolinska University Hospital, 141 86 Stockholm, Sweden. E-mail address: kalle.malmberg{at}ki.se
4 Abbreviations used in this paper: KIR, killer cell Ig-like receptor; GVL, graft-versus-leukemia; SCT, stem cell transplantation; GVHD, graft-vs-host disease.
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