Expansion of functionally skewed CD56-negative NK cells in chronic hepatitis C virus infection: correlation with outcome of pegylated IFN-alpha and ribavirin treatment.
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-1beta, IFN-gamma, TNF-alpha, and CD107a degranulation. The ability of these cells to mediate three or four of these functions was poor; expression of MIP-1beta 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-alpha 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-1beta 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-alpha and ribavirin.
Center for Infectious Medicine, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden.
Veronica D
VD
Gonzalez
Karolin
K
Falconer
Niklas K
NK
Björkström
Kim G
KG
Blom
Ola
O
Weiland
Hans-Gustaf
HG
Ljunggren
Annette
A
Alaeus
Johan K
JK
Sandberg
D000328:Adult; D000998:Antiviral Agents / Q000627:therapeutic use; D019002:CD56 Antigen / Q000276:immunology* / Q000378:metabolism; D018959:CD57 Antigens / Q000276:immunology / Q000378:metabolism; D015550:Cell Degranulation / Q000187:drug effects / Q000276:immunology; D054407:Chemokine CCL4 / Q000276:immunology* / Q000378:metabolism; D005260:Female; D019698:Hepatitis C, Chronic / Q000188:drug therapy / Q000276:immunology*; D006801:Humans; D016898:Interferon-alpha / Q000627:therapeutic use*; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D016131:Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism / Q000821:virology; D052118:Lysosomal-Associated Membrane Protein 1 / Q000276:immunology / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000276:immunology / Q000378:metabolism; D054353:Perforin / Q000276:immunology / Q000378:metabolism; D055607:Receptors, Natural Killer Cell / Q000276:immunology / Q000378:metabolism; D012254:Ribavirin / Q000627:therapeutic use*; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000378:metabolism
D000998:Antiviral Agents; C066507:CCL4 protein, human; D019002:CD56 Antigen; D018959:CD57 Antigens; D054407:Chemokine CCL4; D016898:Interferon-alpha; C527085:KLRK1 protein, human; D052118:Lysosomal-Associated Membrane Protein 1; D055655:NK Cell Lectin-Like Receptor Subfamily K; D055607:Receptors, Natural Killer Cell; D014409:Tumor Necrosis Factor-alpha; D054353:Perforin; D012254:Ribavirin; D007371:Interferon-gamma