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Human Cytomegalovirus Differentially Controls B Cell and T Cell Responses through Effects on Plasmacytoid Dendritic Cells¹

Stefania Varani^*,, Madeleine Cederarv^*, Sari Feld^*, Charlotte Tammik^*, Giada Frascaroli^,, Maria P. Landini and Cecilia Söderberg-Nauclér^2,*

^* Department of Medicine, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden; Department of Clinical and Experimental Medicine, Section of Microbiology, University of Bologna, Bologna, Italy; Department of Virology, University of Ulm, Ulm, Germany

Plasmacytoid dendritic cells (PDCs), the main producers of type I IFN in response to viral infection, are essential in antiviral immunity. In this study, we assessed the effect of human CMV (HCMV) infection on PDC function and on downstream B and T cell responses in vitro. HCMV infection of human PDCs was nonpermissive, as immediate-early but not late viral Ags were detected. HCMV led to partial maturation of PDCs and up-regulated MHC class II and CD83 molecules but not the costimulatory molecules CD80 and CD86. Regardless of viral replication, PDCs secreted cytokines after contact with HCMV, including IFN- secretion that was blocked by inhibitory CpG, suggesting an engagement of the TLR7 and/or TLR9 pathways. In the presence of B cell receptor stimulation, soluble factors produced by HCMV-matured PDCs triggered B cell activation and proliferation. Through PDC stimulation, HCMV prompted B cell activation, but only induced Ab production in the presence of T cells or T cell secreted IL-2. Conversely, HCMV hampered the allostimulatory ability of PDCs, leading to decreased proliferation of CD4⁺ and CD8⁺ T cells. These findings reveal a novel mechanism by which HCMV differentially controls humoral and cell-mediate immune responses through effects on PDCs.

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 Heart-Lung Foundation (199941305, 200241138, 20030055, and 20050266), King Gustaf V’s 80-Year Anniversary Foundation, Swedish Research Council (K2004-16X-12615-07A), Konung Gustaf V’s och Drottning Victorias Foundation, Groschinsky’s Foundation, Pfizer, Swedish Cancer Foundation (060253), and Children’s Cancer Foundation (05/100). C.S.-N. is a fellow of the Royal Swedish Academy of Science, Sweden.

² Address correspondence and reprint requests to Dr. Cecilia Söderberg-Nauclér, Center for Molecular Medicine, L8:03, Karolinska Hospital, Stockholm, Sweden. E-mail address: cecilia.naucler{at}ki.se

³ Abbreviations used in this paper: HCMV, human CMV; DC, dendritic cell; MDC, myeloid dendritic cell; PDC, plasmacytoid dendritic cell; Mo-DC, monocyte-derived DC; ODN, oligodeoxynucleotide; BDCA, blood dendritic cell antigen; MOI, multiplicity of infection; p.i., postinfection; IE, immediate-early Ag; MFI, mean channel fluorescence intensity.