L Particles Transmit Viral Proteins from Herpes Simplex Virus 1-Infected Mature Dendritic Cells to Uninfected Bystander Cells, Inducing CD83 Downmodulation

Abstract

Mature dendritic cells (mDCs) are known as the most potent antigen-presenting cells (APCs) since they are also able to prime/ induce naive T cells. Thus, mDCs play a pivotal role during the induction of antiviral immune responses. Remarkably, the cell surface molecule CD83, which was shown to have costimulatory properties, is targeted by herpes simplex virus 1 (HSV-1) for viral immune escape. Infection of mDCs with HSV-1 results in downmodulation of CD83, resulting in reduced T cell stimulation. In this study, we report that not only infected mDCs but also uninfected bystander cells in an infected culture show a significant CD83 reduction. We demonstrate that this effect is independent of phagocytosis and transmissible from infected to uninfected mDCs. The presence of specific viral proteins found in these uninfected bystander cells led to the hypothesis that viral proteins are transferred from infected to uninfected cells via L particles. These L particles are generated during lytic replication in parallel with full virions, called H particles. L particles contain viral proteins but lack the viral capsid and DNA. Therefore, these particles are not infectious but are able to transfer several viral proteins. Incubation of mDCs with L particles indeed reduced CD83 expression on uninfected bystander DCs, providing for the first time evidence that functional viral proteins are transmitted via L particles from infected mDCs to uninfected bystander cells, thereby inducing CD83 downmodulation. Dendritic cells (DCs) are known as the most potent antigenpresenting cells (APCs) due to their unique ability to prime naive T cells. Thus, they are vital to induce effective antiviral immune responses. In their immature state, DCs reside as sentinels of the immune system in almost all peripheral tissues until they encounter and take up antigens, resulting in maturation of DCs. As a consequence, expression of major histocompatibility complex (MHC) classes I and II as well as of costimulatory molecules, such as CD40, CD80, CD86, and also CD83, is strongly induced (1-3). As CD83 is not expressed on immature, tolerogenic DCs but is highly upregulated during DC maturation, this protein has become one of the best surface markers for mature DCs (3-5). Nevertheless, CD83 is also expressed on subsets of activated T cells, B cells, granulocyte precursor cells, myelocytes, neutrophils, and thymus epithelial cells as well as on regulatory T cells (5-10).In addition to this membrane-bound CD83 molecule (mCD83), a soluble form of CD83 (sCD83), consisting of the extracellular Ig domain of mCD83, also has been described previously (11,12). This soluble form, which was shown to possess potent immunosuppressive properties, is released from activated DCs as well as from B cells and can be detected at low levels in sera of healthy individuals (11) and at highly elevated concentrations in patients suffering from malignant disorders (12). Using animal models, it could be demonstrated that a recombinant expressed sCD83 molecule inhibits disea...

The CD83 Molecule – An Important Immune Checkpoint

“…Within the tripartite gene expression cascade of HSV-1, the immediate early gene product infected cell protein 0 (ICP0) was proven to be essential and sufficient to induce the proteasome-dependent, but ubiquitin-independent, CD83 degradation in mDCs (76). Besides the loss of CD83 protein expression on directly HSV-1-infected mDCs, it has been reported that uninfected bystander mDCs also display a severe reduction of CD83 (77). This bystander effect was attributed to so-called L-particles, which are released by infected cells upon an HSV-1 infection and are non-infectious themselves, due to the lack of the DNA-containing capsid.…”

Nsp1α of Porcine Reproductive and Respiratory Syndrome Virus Strain BB0907 Impairs the Function of Monocyte-Derived Dendritic Cells via the Release of Soluble CD83

“…The plates were incubated in darkness for 15 min at 25°C. The reaction was stopped with 2 M H 2 SO 4 , and the absorbance was measured at 450 nm using a microplate absorbance reader (BioTec, USA) (65,66).…”

Virus-Like Vesicles of Kaposi's Sarcoma-Associated Herpesvirus Activate Lytic Replication by Triggering Differentiation Signaling

“…have also shown that L-particles are able to facilitate HSV-1 infection (13, 53) by enhancing virus replication and impairing the host immune response (52,54). However, no systematic analysis of the protein and RNA compositions of HSV-1 L-particles, or the cellular response from targeted cells, has been carried out.…”