Langerhans cells and viral immunity

Abstract

Langerhans cells (LC) are a unique dendritic cell subset that are located in mucosal stratified squamous epithelium and skin epidermis. Their location is ideally suited for their function as antigen presenting cells that capture invading viruses and induce anti-viral immunity. However, it is becoming evident that the interaction between LC and viruses can result in different responses, depending on the virus and the receptors involved. Here we will discuss the recent data on the similarities and differences in roles of LC in viral immunity to and infection with HIV, herpes simplex and varicella-zoster virus. Although all three viruses interact with LC during initial infection, the effects can be quite different, reflecting differences in biology and pathogenesis. Key words: Dendritic cells Á Langerhans cells Á Infectious diseases Á HIV Á HerpesvirusesSee accompanying mini-review by Kaplan et al. Biology of LC and interactions with virusesThe resident epidermal dendritic cells (DC), Langerhans cells (LC), form a tight network with each other and with the surrounding keratinocytes via E-cadherin in the skin or mucosal stratified squamous epithelium. In the anogenital region they are distributed throughout the anogenital skin and mucosa including vagina, ectocervix as well as male foreskin. In stratified squamous epithelium, LC overlie interstitial or dermal DC [1]. LC can repopulate from local and blood-borne precursors (reviewed by Kaplan et al. in this issue [2]). Similar to other myeloid DC, LC are able to bridge innate and adaptive immunity. They are able to interact directly with microorganisms at the periphery to produce effector cytokines and initiate or restimulate activation of T and B lymphocytes through antigen presentation. LC express different pattern recognition receptors such as C-type lectin receptors (CLR) and Toll-like receptors (TLR), to bind and capture pathogens. These interactions result in activation of intracellular signalling pathways leading to LC activation and cytokine induction. The CLR expressed by skin DC differ by site: Langerin by epidermal LC and DC-SIGN and mannose receptor by dermal DC. LC like other migratory DC are in an immature, highly endocytic state while sessile in the skin/mucosa. However after pathogen binding to TLR and uptake, LC become mature and migratory, downregulating their endocytic and antigen processing capacity. Mature LC migrate to the lymph nodes where they are directly or indirectly involved in presentation of pathogenderived antigens on MHC Class I and II to T cells, resulting in activation of antigen-specific T cells [2][3][4]. Recent studies have raised the possibility that LC may have an immunosuppressive role [5][6][7]. Kaplan et al. [2] showed that contact hypersensitivity was amplified on LC ablation, while Cumberbatch et al.[5] found defective LC mobilisation in patients with psoriasis. Immunosuppression rather than stimulation could be explained, in part, by the maturational process associated with LC migration during steady-state conditions. Jian...

Herpes Simplex Virus Infects Skin γδ T Cells before Langerhans Cells and Impedes Migration of Infected Langerhans Cells by Inducing Apoptosis and Blocking E-Cadherin Downregulation

“…Recent evidence suggests that langerin 2 dDCs and langerin + dDCs are the cutaneous DC subsets that present viral Ag to naive T cells postinfection of murine skin (22,41). LCs are the major APCs in the epidermis and so are likely to be the first DC subset to encounter HSV, because this infection is first confined to the epidermis, but their role in the immune response to acute HSV skin infection remains unclear.…”

A Herpesvirus Virulence Factor Inhibits Dendritic Cell Maturation through Protein Phosphatase 1 and IκB Kinase

“…Upon infection of the mucosal tissues, HSV encounters a variety of cells, including dendritic cells (DCs), that bridge innate and adaptive immunity (7). Immature DCs are able to capture and process viral antigens.…”

Cutaneous RANK–RANKL Signaling Upregulates CD8-Mediated Antiviral Immunity during Herpes simplex Virus Infection by Preventing Virus-Induced Langerhans Cell Apoptosis

“…In the skin, LCs are the obvious primary DC subset likely to be initially involved in HSV-1 antigen uptake, and, accordingly, earlier analyses on the role of LCs in anti-HSV-1 immunity claimed that depletion of LCs before infection leads to increased HSV-1 virulence (Sprecher and Becker, 1986). However, more recently, several studies have conclusively shown that in WT mice, LCs are not the cells presenting HSV-1 antigens to CD8 + T cells and thus are not directly involved in the induction of MHC class I-restricted antiviral immune responses (Allan et al, 2006;Cunningham et al, 2008;Bedoui et al, 2009;Eidsmo et al, 2009;Puttur et al, 2010). After epicutaneous HSV-1 infection, lymph noderesident CD8α + DCs or migratory CD103 + dermal DCs were identified to be the predominant DC population presenting HSV-1 antigens to CD8 + T cells (Allan et al, 2006;Bedoui et al, 2009).…”

“…Interestingly, although LCs are the primary cutaneous antigen-acquiring cells it has been shown that lymph node-resident DCs but not LCs induce MHC class I-restricted antiviral immunity and the priming of HSV-1-specific CTLs (Allan et al, 2003;Cunningham et al, 2008;Bedoui et al, 2009), most likely because HSV-1-infected LCs appeared to be compromised in their trafficking ability as they failed to downregulate E-cadherin or undergo apoptosis after HSV-1 infection (Bosnjak et al, 2005;Eidsmo et al, 2009;Cunningham et al, 2010;Puttur et al, 2010).…”