Immature Monocyte-Derived Dendritic Cells Are Productively Infected with Herpes Simplex Virus Type 1

Abstract

Herpes simplex virus type 1 (HSV-1) initially infects epidermal or mucosal tissues where it replicates and enters the cutaneous sensory axons. It is then retrogradely transported to the neurons of dorsal root ganglia where latent infection is established. Sporadic reactivation of latent virus and transmission to peripheral sites leads to asymptomatic viral shedding or recurrent herpes lesions (41, 50). Symptomatic recurrences are dependent on the levels of local immunity at the periphery and are principally controlled by cell-mediated responses via direct T-cell effector function and cytokine release (24,34,37,45). CD4 ϩ T cells are the initial infiltrating cells in the recurrent lesion, followed by CD8 ϩ cells (9). An immediate-early gene product, ICP47, inhibits major histocompatibility complex (MHC) class I-mediated antigen presentation by binding via its N terminus to the transporter-associated protein (TAP) (1,13,18,49,52). This ICP47-TAP complex prevents translocation of the MHC class I-processed peptide complex to the cell surface, which would prevent recognition by CD8 ϩ T cells. However, gamma interferon secreted by CD4 cells reverses the MHC class I downregulation and stimulates MHC class II expression, allowing targeting of HSV-infected epidermal cells by both CD4 ϩ and CD8 ϩ cytotoxic T cells (33). The persistence of HSV-specific CD8 ϩ clones in seropositive individuals, however, suggests their complementary importance to CD4 ϩ T cells in the control of recurrences (35, 36). The early appearance of virus-specific T-cell effectors depends on prompt signaling from antigen-presenting cells, such as dendritic cells (DC), B cells, or macrophages. The strategic positioning of Langerhans cells in the skin and mucosa identifies them as the most likely antigen-presenting DC to have the earliest contact with the incoming virus.DC form a network of bone marrow-derived antigen-presenting cells that are required for the initiation of adaptive immune responses. DC can be found in virtually all peripheral tissues and are characterized by the CD1a ϩ HLA-DR ϩ CD80 ϩ CD86 ϩ phenotype (3, 17). The capacity of DC to stimulate T cells is closely related to their maturation stage (40). Immature DC, exemplified by epidermal Langerhans cells, act as sentinels and are highly specialized at antigen uptake and processing but are poor stimulators of primary immune responses (3,17,43). A variety of immune stimuli induce phenotypic and functional changes to resting DC as they migrate out of the tissues and into secondary lymphoid organs. Mature DC no longer take up and process antigen but upregulate MHC class I and II costimulatory and adhesion molecules, effectively boosting their ability to present processed peptides to antigen-specific T cells. During the process of maturation, DC also express CD83, a maturation marker not found on resting immature DC such as Langerhans cells (54). Terminal maturation of DC is induced upon contact with T cells via CD40 ligation (6). Experimental studies of human Langerhans cells have been hamp...

Langerhans cells and viral immunity

“…HSV infection results in asynchronous downregulation of the key costimulatory molecules CD40, CD80, CD83, and CD86, preventing proper maturation of the DC, whereas, exposure to UV-inactivated HSV results in upregulation of these molecules [59,61]. Furthermore, HSV-infected DC are resistant to further maturation stimuli supplied by LPS, TNF-a or CD40L [62].…”

“…In most other cell types, HSV-1 produces anti-apoptotic effects, whereas in DC, both HSV-1 and HSV-2 induce apoptosis progressively throughout the cell sheet over 24 h [59,67]. Furthermore, HSV-2 induces apoptosis more rapidly than HSV-1.…”

“…Furthermore, HSV-infected DC are resistant to further maturation stimuli supplied by LPS, TNF-a or CD40L [62]. Interestingly, MHC class I is not downregulated on infected monocyte-derived DC, unlike most other infected cells [59]. The inability of HSV-1 ICP47 to interfere with MHC class I expression is most likely the consequence of the innately high levels of translocator associated proteins TAP in DC.…”

“…Similar to HIV-1, the C-type lectin DC-SIGN functions as an attachment receptor on immature DC that enhances DC infection [58]. Mature DC are non-productively/ abortively infected [59,60]. However, mature DC are not usually found at the cutaneous sites of HSV infection, and therefore studies examining immature DC are more relevant.…”

“…Mature DC are non-productively/ abortively infected [59,60]. However, mature DC are not usually found at the cutaneous sites of HSV infection, and therefore studies examining immature DC are more relevant.HSV infection results in asynchronous downregulation of the key costimulatory molecules CD40, CD80, CD83, and CD86, preventing proper maturation of the DC, whereas, exposure to UV-inactivated HSV results in upregulation of these molecules [59,61]. Furthermore, HSV-infected DC are resistant to further maturation stimuli supplied by LPS, TNF-a or CD40L [62].…”