A Neuron-Specific Role for Autophagy in Antiviral Defense against Herpes Simplex Virus

SummaryType I interferons (IFNs) are considered to be the universal mechanism by which viral infections are controlled. However, many IFN-stimulated genes (ISGs) rely on antiviral pathways that are toxic to host cells, which may be detrimental in nonrenewable cell types, such as neurons. We show that dorsal root ganglionic (DRG) neurons produced little type I IFNs in response to infection with a neurotropic virus, herpes simplex type 1 (HSV-1). Further, type I IFN treatment failed to completely block HSV-1 replication or to induce IFN-primed cell death in neurons. We found that DRG neurons required autophagy to limit HSV-1 replication both in vivo and in vitro. In contrast, mucosal epithelial cells and other mitotic cells responded robustly to type I IFNs and did not require autophagy to control viral replication. These findings reveal a fundamental difference in the innate antiviral strategies employed by neurons and mitotic cells to control HSV-1 infection

Differential roles of migratory and resident DCs in T cell priming after mucosal or skin HSV-1 infection

Although mucosal surfaces represent the main portal of entry for pathogens, the mechanism of antigen presentation by dendritic cells (DCs) that patrol various mucosal tissues remains unclear. Instead, much effort has focused on the understanding of initiation of immune responses generated against antigens delivered by injection. We examined the contributions of migratory versus lymph node–resident DC populations in antigen presentation to CD4 and CD8 T cells after needle injection, epicutaneous infection, or vaginal mucosal herpes simplex virus (HSV) 1 infection. We show that upon needle injection, HSV-1 became lymph-borne and was rapidly presented by lymph node–resident DCs to CD4 and CD8 T cells. In contrast, after vaginal HSV-1 infection, antigens were largely presented by tissue-derived migrant DCs with delayed kinetics. In addition, migrant DCs made more frequent contact with HSV-specific T cells after vaginal infection compared with epicutaneous infection. Thus, both migrant and resident DCs play an important role in priming CD8 and CD4 T cell responses, and their relative importance depends on the mode of infection in vivo

Th1 or Th2 balance regulated by interaction between dendritic cells and NKT cells

If Th1 or Th2 polarization could be artificially manipulated, effective immune responses would be generated depending on nature of the targets. In this study we attempted to regulate CD40 expressions on dendritic cells (DCs) in order to modify the T cell response. It was found that reducing agents selectively inhibited surface expression of CD40 on DCs. This finding may provide a new strategy of DC-mediated modulation of the Th1/Th2 balance. It was also shown that NKT-produced Th1/Th2 cytokine balance was under control of negative feedback loop through DCs. Th1 cytokine-pretreated DCs mainly induced Th2 cytokine production, whereas Th2 cytokine-pretreated DCs induced Th1 cytokine production by α-galactosylceramide-stimulated NKT cells. The negative feedback regulation system could be applicable to therapeutics of various diseases based on immunological disorders