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Blood, 16 April 2009, Vol. 113, No. 16, pp. 3875-3884.
Prepublished online as a Blood First Edition Paper on January 28, 2009; DOI 10.1182/blood-2008-09-177055.
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Submitted September 8, 2008
Accepted January 1, 2009
Breaking tolerance to self, circulating natural killer cells expressing inhibitory KIR for non-self HLA exhibit effector function following T-cell depleted allogeneic hematopoietic cell transplantation
Junli Yu, Jeffrey M. Venstrom, Xiao-Rong Liu, Richard O'Reilly, James Pring, Reenat S. Hasan, and Katharine C. Hsu*
Immunology Program, Sloan-Kettering Institute for Cancer Research, New York, NY, United States
Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY, United States
Department of Pediatrics, Memorial Sloan-Kettering Cancer Center, New York, NY, United States
* Corresponding author; email: hsuk{at}mskcc.org.
Alloreactive NK cells are important influence on hematopoietic stem cell transplantation (HSCT) outcome. In HLA-mismatched HSCT, alloreactivity occurs when licensed donor NK cells expressing inhibitory killer Ig-like receptors (KIR) for donor MHC class I ligands recognize the lack of the class I ligands in the mismatched recipient ("missing self"). Studies in HLA-matched HSCT, however, have also demonstrated improved outcome in patients lacking class I ligands for donor inhibitory KIR ("missing ligand"), indicating that classically non-licensed donor NK cells expressing KIR for non-self MHC class I ligands may exhibit functional competence in HSCT. We examined NK function in 16 recipients of T-cell depleted allografts from HLA-identical or KIR-ligand matched donors following myeloablative therapy. Following HSCT, non-licensed NK cells expressing inhibitory KIR for non-self class I exhibit robust intracellular IFN- and cytotoxic response to target cells lacking cognate ligand, gradually becoming tolerized to self by day 100. These findings could not be correlated with cytokine environment or phenotypic markers of NK development, nor could they be attributed to non-KIR receptors such as CD94/NKG2A. These findings confirm that NK alloreactivity can occur in HLA-matched HSCT, where tolerance to self is either acquired by the stem-cell derived NK cell after exiting the bone marrow or where tolerance to self can be temporarily overcome.
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