The precise role of each of the seven individual CD11c؉ dendritic cell subsets (DCs) identified to date in the response to viral infections is not known. DCs serve as critical links between the innate and adaptive immune responses against many pathogens, including herpes simplex virus type 1 (HSV-1). The role of DCs as mediators of resistance to HSV-1 infection was investigated using CD11c-diphtheria toxin (DT) receptor-green fluorescent protein transgenic mice, in which DCs can be transiently depleted in vivo by treatment with low doses of DT. We show that ablation of DCs led to enhanced susceptibility to HSV-1 infection in the highly resistant C57BL/6 mouse strain. Specifically, we showed that the depletion of DCs led to increased viral spread into the nervous system, resulting in an increased rate of morbidity and mortality. Furthermore, we showed that ablation of DCs impaired the optimal activation of NK cells and CD4؉ and CD8 ؉ T cells in response to HSV-1. These data demonstrated that DCs were essential not only in the optimal activation of the acquired T-cell response to HSV-1 but also that DCs were crucial for innate resistance to HSV-1 infection.Based on serological evidence, it is estimated that 60 to 80% of the adult population is infected with herpes simplex virus type 1 (HSV-1) (46). Most infected individuals remain asymptomatic. Of symptomatic individuals, clinical presentation ranges from mild illness, such as the development of orofacial vesicular lesions, all the way to life-threatening systemic complications, such as hepatitis and encephalitis (39). The outcome of infection is known to be influenced by both specific and nonspecific genetically linked host defense mechanisms (32). The immune system is particularly important in controlling HSV-1 infection in both the periphery and the nervous system, although the events that initiate this immunity in humans are not very well understood. Underlying immunosuppression does not appear to explain the distinct outcomes of host-virus interaction. Rather, the observed range in clinical outcomes appears to reflect differences in intrinsic resistance to infection.Studies using inbred strains of mice have revealed critical insights into the immunological basis for resistance to . Specifically, a range in innate resistance to systemic, lethal HSV-1 infection exists and has subsequently led to the grouping of inbred mice into resistant, moderately susceptible, and susceptible categories based upon the levels of virus required to cause death. In all cases examined, mice of the C57 background (C57BL/6 and C57BL/10) are most resistant and best able to effectively control HSV-1 infection (35).Human and murine studies suggest that the innate immune response, specifically the ability to produce elevated levels of type I interferon (IFN) at early time points, provides a threshold of resistance to acute HSV-1 infection (44).

No abstract

The role of CD4؉ helper T cells in modulating the acquired immune response to herpes simplex virus type 1 (HSV-1) remains ill defined; in particular, it is unclear whether CD4 ؉ T cells are needed for the generation of the protective HSV-1-specific CD8؉ -T-cell response. This study examined the contribution of CD4 ؉ T cells in the generation of the primary CD8؉ -T-cell responses following acute infection with HSV-1. The results demonstrate that the CD8 ؉ -T-cell response generated in the draining lymph nodes of CD4 ؉ -T-cell-depleted C57BL/6 mice and B6-MHC-II ؊/؊ mice is quantitatively and qualitatively distinct from the CD8 ؉ T cells generated in normal C57BL/6 mice. Phenotypic analyses show that virus-specific CD8 ؉ T cells express comparable levels of the activation marker CD44 in mice lacking CD4 ؉ T cells and normal mice. In contrast, CD8؉ T cells generated in the absence of CD4 ؉ T cells express the interleukin 2 receptor ␣-chain (CD25) at lower levels. Importantly, the CD8 ؉ T cells in the CD4؉ -T-cell-deficient environment are functionally active with respect to the expression of cytolytic activity in vivo but exhibit a diminished capacity to produce gamma interferon and tumor necrosis factor alpha. Furthermore, the primary expansion of HSV-1-specific CD8 ؉ T cells is diminished in the absence of CD4؉ -T-cell help. These results suggest that CD4 ؉ -T-cell help is essential for the generation of fully functional CD8 ؉ T cells during the primary response to HSV-1 infection.

No abstract