As originally demonstrated for the interleukin 1 (IL-1) type II receptor, some primary proinflammatory cytokines from the IL-1 and tumor necrosis factor families are regulated by decoy receptors that are structurally incapable of signaling. Here we report that concomitant exposure to proinflammatory signals and IL-10 generates functional decoy receptors in the chemokine system. Inflammatory signals, which cause dendritic cell (DC) maturation and migration to lymphoid organs, induce a chemokine receptor switch, with down-regulation of inflammatory receptors (such as CCR1, CCR2, CCR5) and induction of CCR7. Concomitant exposure to lipopolysaccharide (LPS) and IL-10 blocks the chemokine receptor switch associated with DC maturation. LPS + IL-10-treated DCs showed low expression of CCR7 and high expression of CCR1, CCR2 and CCR5. These receptors were unable to elicit migration. We provide evidence that uncoupled receptors, expressed on LPS + IL-10-treated cells, sequester and scavenge inflammatory chemokines. Similar results were obtained for monocytes exposed to activating signals and IL-10. Thus, in an inflammatory environment, IL-10 generates functional decoy receptors on DC and monocytes, which act as molecular sinks and scavengers for inflammatory chemokines.

No abstract

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-α 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.

H uman cytomegalovirus (HCMV) (1) is a herpesvirus that persistently infects the majority of the human population. After primary infection, HCMV remains lifelong in its host, being able to avoid clearance from the immune system. Whether HCMV persists in a truly latent state (defined as persistence in the absence of detectable infectious virus particles) or in a continuous lowlevel replication state is not clear (2, 3). However, the observation that around 10% of CD8 ϩ and CD4 ϩ T cells in the peripheral blood of healthy seropositive persons are committed to anti-HCMV responses (4) argues for continuous restimulation of T cells with antigens produced during phases of viral reactivation or low-grade active replication. Antigen recognition and T-cell activation are defined by the tightly regulated interaction between the T-cell receptor (TCR) and antigenic peptides that are presented in the context of class I or class II major histocompatibility complex (MHC) molecules on the surface of antigen-presenting cells (APC). A number of studies have shown that the most potent APC, i.e., dendritic cells (DC), are severely impaired by HCMV in their antigen presentation, migration, and T-cell activation capabilities (reviewed in reference 5). How APC that are altered in their function can trigger and maintain a massive HCMVspecific T-cell repertoire is difficult to explain. Due to their dual nature of being permissive to HCMV infection (6-9) and being professional APC (10), macrophages (M) would represent the ideal site for antigen production, processing, and presentation to the adaptive branch of the immune system during HCMV infection.We and others have shown that M are highly susceptible to HCMV infection in vitro and that these cells produce viral progeny (11)(12)(13)(14)(15). Nevertheless, the majority of previous studies did not take into account that, in the context of immunity and inflammation, M acquire different activation states. For the sake of simplicity, M have been classified along what could be viewed as a linear scale, in which M1 M represent one extreme and M2 M the other (16). In this classification, the M1 designation refers to classically activated M, namely, cells that are capable of sustaining the immune response to pathogens through release of proinflammatory factors as well as efficient antigen presentation and T-cell stimulation. The M2 designation refers to alternatively activated M, namely, a very heterogeneous group of cells contributing to resolution of inflammation, tissue repair, extracellular matrix remodeling, and pathogen scavenging. Recent evidence indicates different susceptibilities of M1 and M2 M to HCMV infection (17,18). Nevertheless, the course of HCMV infection in these two types of M as well as the M-specific contribution to the adaptive immune response against HCMV still remains elusive.In this study, we addressed how M polarization defines HCMV susceptibility and how HCMV infection modifies M activation. We also determined the capability of HCMV-infected M to present antigen to ...