Research Article: The Role of Plasmacytoid Dendritic Cells in Innate and Adaptive Immune Responses against Alpha Herpes Virus Infections

Date Published: March 31, 2011

Publisher: Hindawi Publishing Corporation

Author(s): Philipp Schuster, Jan Bernardin Boscheinen, Karin Tennert, Barbara Schmidt.


In 1999, two independent groups identified plasmacytoid dendritic cells (PDC) as major type I interferon- (IFN-) producing cells in the blood. Since then, evidence is accumulating that PDC are a multifunctional cell population effectively coordinating innate and adaptive immune responses. This paper focuses on the role of different immune cells and their interactions in the surveillance of alpha herpes virus infections, summarizes current knowledge on PDC surface receptors and their role in direct cell-cell contacts, and develops a risk factor model for the clinical implications of herpes simplex and varicella zoster virus reactivation. Data from studies involving knockout mice and cell-depletion experiments as well as human studies converge into a “spider web”, in which the direct and indirect crosstalk between many cell populations tightly controls acute, latent, and recurrent alpha herpes virus infections. Notably, cells involved in innate immune regulations appear to shape adaptive immune responses more extensively than previously thought.

Partial Text

The human alpha herpes viruses comprise three different viruses: herpes simplex virus type 1 (HSV-1), type 2 (HSV-2), and varicella zoster virus (VZV) [1]. These highly cytopathic viruses are characterized by a short replication cycle, a broad cell tropism, and an efficient spread in cell culture. Importantly, they exhibit a distinct neurotropism, which, after primary infection at mucocutaneous sites, guides the viral particles along the peripheral sensory nerves to the dorsal root ganglia or the trigeminal ganglion, where they establish latent infection. Under circumstances of local or systemic immune suppression, alpha herpes viruses are reactivated and transported the same way, but in the reverse direction, to the epithelial surfaces. Primary HSV-1 and HSV-2 infections can manifest as stomatitis aphthosa, herpetic whitlow, and neonatal herpes acquired by passage through the maternal birth canal [2]. Reactivations are well known as cold sores, corneal, and genital herpes. Primary and recurrent VZV infections manifest as chickenpox and shingles, respectively [3]. In rare cases, alpha herpes viruses cause severe diseases such as encephalitis, acute retinal necrosis, and life-threatening systemic infections. It still remains a mystery why only a few individuals in the large cohort of seropositives are so severely affected by these viruses.

The current literature on the control of acute and latent herpes virus infections is summarized in Figure 1. There is not only evidence that single cell populations play a direct role in the suppression of alpha herpes virus replication, but cells interact with each other and across the innate-adaptive barrier in mediating efficient surveillance.

What is the evidence that PDC—in addition to secretion of type I IFN and proinflammatory cytokines—shape the immune response by direct cell-cell contact? The antigen-presenting properties of PDC, which we are just beginning to understand, were recently addressed in an excellent review [83]. The PDC surface receptors are increasingly coming into the focus of scientific research [84–88]. However, data about the function of PDC surface receptors in alpha herpes virus infections are scarce, and in most cases the function is deduced from the regulation of expression upon stimulation of PDC with HSV, other viruses or CpG, and from the function of these surface receptors on other cell populations.

One of the best studied models of alpha herpes virus reactivation from latency is the acute retinal necrosis (ARN). Roughly one and two thirds of cases are caused by reactivation of HSV and VZV, respectively. Clinical course, treatment options and therapy outcome of this severe disease were recently reviewed [134–136]. The vasculitis, retinal necrosis, and intraocular inflammation start in the periphery and rapidly progress circumferentially, mostly affecting nonimmunocompromised patients at a frequency of 0.5 cases per 1 million. Current therapies combine antiviral and anti-inflammatory drugs with surgical intervention. An early vitrectomy with silicon oil instillation is associated with a lower incidence of retinal detachment compared to conservative treatment; however, the overall visual prognosis is poor [137, 138]. The cause appears to be, besides retinal detachment, herpes virus-associated retinal ischemia and atrophy of the optic nerve [139].

What have we learned from the published data ? General conclusions are shortened in terms of the variability of animal models used: different animal strains, different viruses, and different modes of infection may lead to different conclusions. Another caveat is that mouse data do not readily translate into the human system, for which the data are still limited. Yet, three important conclusions can be drawn. First, many cell populations are involved to keep primary and recurrent alpha herpes virus infections under control, which may reflect how seriously these cytopathic infections are taken by the immune system. A second conclusion is that the textbook knowledge of innate cells controlling primary infection and adaptive immunity supervising latent alpha herpes virus infections is no longer clearcut. Cells involved in innate immune regulations appear to shape adaptive immune responses more extensively than previously thought. Is there a master regulator in this system, for example, the two dendritic cell populations that coordinate each other and all other cells ? Or does each component of the immune system substitute for another in some respect ? A third conclusion is that interactions of different cell populations via soluble factors and in particular via surface receptors appear to be crucial to fight against alpha herpes virus infections [152, 153], which, if not controlled efficiently, will cause severe disabling diseases.