Patients with systemic lupus erythematosus (SLE) show an over-expression of Type I Interferon (IFN) responsive genes called “Interferon Signature”. We found that the B6.NZMSle1/Sle2/Sle3 (Sle1,2,3) lupus-prone mice also express an Interferon Signature compared to non autoimmune C57BL/6 mice. In vitro, myeloid dendritic cells (mDCs)(GM-CSF bone marrow-derived BMDCs) from Sle1,2,3 mice constitutively over-expressed IFN responsive genes such as IFNb, Oas-3, Mx-1, ISG-15 and CXCL10, and the members of IFN signaling pathway STAT1, STAT2, and IRF7. The Interferon Signature was similar in Sle1,2,3 BMDCs from young, pre-autoimmune mice and from mice with high titers of autoantibodies, suggesting that the Interferon Signature in mDCs precedes disease onset and it is independent from the autoantibodies. Sle1,2,3 BMDCs hyper-responded to stimulation with IFNa and the TLR7 and TLR9 agonists R848 and CpGs. We propose that this hyper-response is induced by the Interferon Signature and only partially contributes to the Signature, since oligonucleotides inhibitory for TLR7 and TLR9 only partially suppressed the constitutive Interferon Signature and pre-exposure to IFNa induced the same hyper-response in wild type BMDCs than in Sle1,2,3 BMDCs. In vivo, mDCs and with lesser extent T and B cells from young pre-diseased Sle1,2,3 mice also expressed the Interferon Signature, although they lacked the strength that BMDCs showed in vitro. Sle1,2,3 plasmacytoid DCs expressed the Interferon Signature in vitro but not in vivo, suggesting that mDCs may be more relevant before disease onset. We propose that Sle1,2,3 mice are useful tools to study the role of the Interferon Signature in lupus pathogenesis.

To activate T cells effectively, dendritic cells (DCs) must provide three separate signals, MHC-Ag, costimulatory molecules (such as CD80 and CD86), and proinflammatory cytokines (such as IL-12). These three signals are up-regulated in the presence of “danger signals” such as LPS or viral nucleic acids. Evidence suggests that DCs providing only the first two of these signals cannot successfully stimulate T cells. Apoptotic cells have been proposed to suppress DC immunogenicity through the ligation of apoptotic cell receptors. Complement receptor 3 (CR3) and CD36 have been suggested to be important in this process, although the mechanism by which this modulation occurs is still unclear. We demonstrate that ligation of CR3, but not CD36, directs DCs to increase surface MHC and costimulatory molecules, while suppressing inflammatory cytokine release. CR3 modulation of DCs does not require a type I IFN response, does not involve the specific regulation of the MyD88- or Toll/IL-1R domain-containing adaptor-inducing IFN-β-dependent TLR signaling pathways, and occurs even in the absence of danger signals. The functional outcome of this process is poor Ag-specific stimulation of CD4 and CD8 T cells by CR3-ligated DCs both in naive response as well as upon subsequent challenge with normal DCs. We propose that CR3 provides a “nondanger” signal that suppresses the stimulatory capacity of DCs.

The viral infectivity factor gene (vif) of HIV-1 increases the infectivity of viral particles by inactivation of cellular anti-viral factors, and supports productive viral replication in primary human CD4 T cells and in certain non-permissive T cell lines. Here, we demonstrate that Vif also contributes to the arrest of HIV-1 infected cells in the G(2) phase of the cell cycle. Viruses deleted in Vif or Vpr induce less cell cycle arrest than wild-type virus, while cells infected with HIV-1 deleted in both Vif and Vpr have a cell cycle profile equivalent to that of uninfected cells. Furthermore, expression of Vif alone induces accumulation of cells in the G(2) phase of the cell cycle. These data demonstrate a novel role for Vif in cell cycle regulation and suggest that Vif and Vpr independently drive G(2) arrest in HIV-1 infected cells. Our results may have implications for the actions and interactions of key HIV-1 accessory proteins in AIDS pathogenesis.