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This Article Full Text Full Text (PDF) All Versions of this Article: jimmunol.0901437v1 183/10/6612    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 Gonzalez, V. D. Articles by Sandberg, J. K. PubMed PubMed Citation Articles by Gonzalez, V. D. Articles by Sandberg, J. K.

Expansion of Functionally Skewed CD56-Negative NK Cells in Chronic Hepatitis C Virus Infection: Correlation with Outcome of Pegylated IFN- and Ribavirin Treatment¹

Veronica D. Gonzalez,^* Karolin Falconer,^2* Niklas K. Björkström,^2* Kim G. Blom,^* Ola Weiland, Hans-Gustaf Ljunggren,^* Annette Alaeus, and Johan K. Sandberg^3*

^*Center for Infectious Medicine, Department of Medicine and Division of Infectious Diseases, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden; and Unit of Infectious Diseases, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Solna, Stockholm, Sweden

NK cells are important innate immune effector cells, normally characterized as CD56⁺CD3^– lymphocytes. In this study, we report that CD56^–CD16⁺ NK cells expand in many patients with chronic hepatitis C virus infection. These CD56^– NK cells were functionally impaired with respect to cytokine production upon target cell recognition, in comparison to CD56^dim and CD56^bright NK cell subsets. In particular, CD56^– NK cells were strikingly defective in their polyfunctional response as measured by the coexpression of MIP-1β, IFN-, TNF-, and CD107a degranulation. The ability of these cells to mediate three or four of these functions was poor; expression of MIP-1β alone dominated their response. CD56^– NK cells retained expression of receptors such as the natural cytotoxicity receptors and NKG2D, whereas the expression of CD57 and perforin was lower when compared with CD56^dim NK cells. Interestingly, pretreatment levels of CD56^– NK cells correlated with the outcome of pegylated IFN- and ribavirin treatment. In patients with CD56^– NK cells in the range of healthy subjects, 80% reached a sustained virological response to treatment, whereas only 25% of patients with levels clearly above those in healthy subjects experienced a sustained virological response. Thus, chronic hepatitis C virus infection is associated with an expansion of CD56^– NK cells functionally skewed toward MIP-1β production only. Furthermore, high levels of these cells reveal a disturbance in innate cellular immunity that is associated with an impaired ability to respond to antiviral treatment with IFN- and ribavirin.

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 Research Council, the Swedish International Development Agency, the Swedish Foundation for Strategic Research, the Swedish Physicians against AIDS Research Foundation, and the Karolinska Institutet.

² K.F. and N.K.B. contributed equally.

³ Address correspondence and reprint requests to Dr. Johan K. Sandberg, Center for Infectious Medicine, Department of Medicine, F59, Karolinska Institutet, Karolinska University Hospital Huddinge, 14186 Stockholm, Sweden. E-mail address: johan.sandberg{at}ki.se

⁴ Abbreviations used in this paper: NCR, natural cytotoxicity receptor; HCV, hepatitis C virus; SVR, sustained virological response; peg-IFN-, pegylated IFN-.