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This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: jimmunol.0900541v1 183/3/1789    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Google Scholar Articles by Burt, B. M. Articles by DeMatteo, R. P. PubMed PubMed Citation Articles by Burt, B. M. Articles by DeMatteo, R. P.

The Lytic Potential of Human Liver NK Cells Is Restricted by Their Limited Expression of Inhibitory Killer Ig-Like Receptors¹

Bryan M. Burt^*, George Plitas^*, Zeguo Zhao, Zubin M. Bamboat^*, Hoang M. Nguyen^*, Bo Dupont and Ronald P. DeMatteo^2,*

^* Hepatopancreatobiliary Service, Memorial Sloan-Kettering Cancer Center, New York, NY 10065; and Immunology Program, Sloan-Kettering Institute, New York, NY 10065

The human liver is enriched in NK cells which are potent effectors of the innate immune system. We have determined that liver NK cells freshly isolated from surgical specimens from patients with hepatic malignancy have less cytolytic activity than autologous blood NK cells. This difference was due to a higher proportion of CD16^– NK cells in the liver and reduced cytotoxicity by CD16⁺ liver NK cells compared with their blood counterparts. CD16⁺ liver NK cells had similar expression of activating NK receptors and had similar intracellular granzyme B and perforin content compared with CD16⁺ blood NK cells. CD16⁺ liver NK cells contained a reduced fraction of cells with inhibitory killer Ig-like receptors specific for self-MHC class I (self-killer Ig-related receptor (KIR)) and an increased fraction of self-KIR^negNKG2A^pos and self-KIR^negNKG2A^neg cells. Using single-cell analysis of intracellular IFN- production and cytotoxicity assays, we determined that CD16⁺ liver NK cells expressing self-KIR were more responsive to target cells than those cells that did not express self-KIR molecules. CD16⁺ liver NK cells gained cytolytic function when stimulated with IL-2 or cultured with LPS or poly(I:C)-activated autologous liver Kupffer cells. Thus, the human liver contains NK cell subsets which have reduced effector function, but under appropriate inflammatory conditions become potent killers.

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 Grants DK068346 and AI70658 (to R.P.D.), CA23766 (to Z.Z. and B.D.), and CA123938 (to B.M.B.), the William H. Goodwin and Alice Godman Fund and Commonwealth Cancer Foundation for Research/Experimental Therapeutics Center of Memorial Sloan-Kettering Cancer Center, and the Swim Across America Foundation.

² Address correspondence and reprint requests to Dr. Ronald P. DeMatteo, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, Box 203, New York, NY 10065. E-mail address: dematter{at}mskcc.org

³ Abbreviations used in this paper: DC, dendritic cell; MHC-I, MHC class I; KIR, killer Ig-like receptor; LMNC, liver mononuclear cell; KC, Kupffer cell.

⁴ The online version of this article contains supplemental material.