Dendritic cells (DC) are a heterogeneous family of innate immune cells with crucial functions in host defense against invading pathogens, including viruses. Immature myeloid DC such as Langerhans cells (LC) and dermal DC are strategically located in the skin and mucosae, where they are among the first cell types to encounter viruses during entry. Contact with pathogens is followed by their maturation and migration to the secondary lymphoid organs, where they stimulate naïve T and B cells to proliferate and differentiate into CD8+ or CD4+ T lymphocytes, and into antibody-producing plasma cells. Plasmacytoid DC, by contrast, are mostly found in blood, where they exert potent anti-viral functions by producing vast amounts of interferon-a and -ß.
Both types of DC play pivotal roles in herpesvirus infections.
Horizontal transmission of all herpesviruses occurs primarily by contact with host mucosae, where virions are bound to encounter resident myeloid DC. While this interaction ultimately leads to the generation of lifelong protective immunity, in the short term it may promote host colonization instead.
A number of studies have shown that in vitro-derived immature monocyte-derived DC (MDDC) are permissive to the complete replication cycle of human herpes simplex virus 1 and 2 (HSV-1 and -2), varicella zoster virus (VZV), cytomegalovirus (CMV) and Kaposi’s sarcoma associated herpesvirus (KSHV), but not to Epstein-Barr virus (EBV). Productive infections are accompanied by the blunting of MDDC immunostimulatory abilities (HSV-1, HSV-2, CMV, KSHV), by a loss of cell viability (HSV-1, HSV-2), and by enhanced virus transmission to T cells (VZV). While immature LC are susceptible to infection by HSV-1 and VZV, they remain remarkably resistant to CMV until matured. Maturation is also required for CMV reactivation to occur in LC differentiated from latently infected CD34+ progenitor cells. Finally, detection of EBV, HSV-1 and HSV-2 by plasmacytoid DC was shown to trigger the release of type I interferons, while their direct infection led to functional paralysis. If these findings hold true in vivo, then the release of viral progeny by infected DC in the mucosae, in the afferent lymphatics and in the draining lymph nodes is likely to substantially enhance the rate of herpesvirus dissemination within the host, while the immunosuppressive effects associated with DC infection may support host colonization by other pathogens entering via mucosae, eventually promoting the establishment of multiple infections. The fact that protective immunity against herpesviruses is ultimately achieved, however, indicates that DC functions are not completely ablated by infection. This renders DC’s interactions with herpesviruses highly relevant for the conception of innovative therapies and vaccines against these pathogens.
Here, we wish to compile a collection of original research and review articles focusing on our current understanding of herpesvirus interactions with DC, and on their potential use to develop more effective antiviral therapeutics and vaccines.
Dendritic cells (DC) are a heterogeneous family of innate immune cells with crucial functions in host defense against invading pathogens, including viruses. Immature myeloid DC such as Langerhans cells (LC) and dermal DC are strategically located in the skin and mucosae, where they are among the first cell types to encounter viruses during entry. Contact with pathogens is followed by their maturation and migration to the secondary lymphoid organs, where they stimulate naïve T and B cells to proliferate and differentiate into CD8+ or CD4+ T lymphocytes, and into antibody-producing plasma cells. Plasmacytoid DC, by contrast, are mostly found in blood, where they exert potent anti-viral functions by producing vast amounts of interferon-a and -ß.
Both types of DC play pivotal roles in herpesvirus infections.
Horizontal transmission of all herpesviruses occurs primarily by contact with host mucosae, where virions are bound to encounter resident myeloid DC. While this interaction ultimately leads to the generation of lifelong protective immunity, in the short term it may promote host colonization instead.
A number of studies have shown that in vitro-derived immature monocyte-derived DC (MDDC) are permissive to the complete replication cycle of human herpes simplex virus 1 and 2 (HSV-1 and -2), varicella zoster virus (VZV), cytomegalovirus (CMV) and Kaposi’s sarcoma associated herpesvirus (KSHV), but not to Epstein-Barr virus (EBV). Productive infections are accompanied by the blunting of MDDC immunostimulatory abilities (HSV-1, HSV-2, CMV, KSHV), by a loss of cell viability (HSV-1, HSV-2), and by enhanced virus transmission to T cells (VZV). While immature LC are susceptible to infection by HSV-1 and VZV, they remain remarkably resistant to CMV until matured. Maturation is also required for CMV reactivation to occur in LC differentiated from latently infected CD34+ progenitor cells. Finally, detection of EBV, HSV-1 and HSV-2 by plasmacytoid DC was shown to trigger the release of type I interferons, while their direct infection led to functional paralysis. If these findings hold true in vivo, then the release of viral progeny by infected DC in the mucosae, in the afferent lymphatics and in the draining lymph nodes is likely to substantially enhance the rate of herpesvirus dissemination within the host, while the immunosuppressive effects associated with DC infection may support host colonization by other pathogens entering via mucosae, eventually promoting the establishment of multiple infections. The fact that protective immunity against herpesviruses is ultimately achieved, however, indicates that DC functions are not completely ablated by infection. This renders DC’s interactions with herpesviruses highly relevant for the conception of innovative therapies and vaccines against these pathogens.
Here, we wish to compile a collection of original research and review articles focusing on our current understanding of herpesvirus interactions with DC, and on their potential use to develop more effective antiviral therapeutics and vaccines.
