Relay of herpes simplex virus between Langerhans cells and dermal dendritic cells in human skin.

Min Kim,Naomi R Truong,Lidija Bosnjak,Virginia James,Najla Nasr,Kirstie M Bertram,Norman Olbourne,Andrew N Harman,Kaylene Mckinnon,Shailandra Sawleshwarkar,Anthony L Cunningham,Kerrie J Sandgren,Ralph C Cohen,Erik K Flemington

doi:10.1371/journal.ppat.1004812

Abstract

The mechanism by which immunity to Herpes Simplex Virus (HSV) is initiated is not completely defined. HSV initially infects mucosal epidermis prior to entering nerve endings. In mice, epidermal Langerhans cells (LCs) are the first dendritic cells (DCs) to encounter HSV, but it is CD103+ dermal DCs that carry viral antigen to lymph nodes for antigen presentation, suggesting DC cross-talk in skin. In this study, we compared topically HSV-1 infected human foreskin explants with biopsies of initial human genital herpes lesions to show LCs are initially infected then emigrate into the dermis. Here, LCs bearing markers of maturation and apoptosis formed large cell clusters with BDCA3+ dermal DCs (thought to be equivalent to murine CD103+ dermal DCs) and DC-SIGN+ DCs/macrophages. HSV-expressing LC fragments were observed inside the dermal DCs/macrophages and the BDCA3+ dermal DCs had up-regulated a damaged cell uptake receptor CLEC9A. No other infected epidermal cells interacted with dermal DCs. Correspondingly, LCs isolated from human skin and infected with HSV-1 in vitro also underwent apoptosis and were taken up by similarly isolated BDCA3+ dermal DCs and DC-SIGN+ cells. Thus, we conclude a viral antigen relay takes place where HSV infected LCs undergo apoptosis and are taken up by dermal DCs for subsequent antigen presentation. This provides a rationale for targeting these cells with mucosal or perhaps intradermal HSV immunization.

Highlights

Dendritic cells (DCs) in the skin and mucosa play a major role as sentinels in the detection and uptake of pathogens and initiation of innate and adaptive immune responses [1]
The first immune cells to become infected, Langerhans cells in the epidermis, are not the cells that initiate the immune response, while the dermal dendritic cells thought to be responsible for initiating the immune response are not likely to be infected
Herpes Simplex Virus (HSV) is taken up by the epidermal Langerhans cells that migrate into the dermis, die and are taken up by another subset of dermal dendritic cells—the homologs of those in mice which stimulate HSV-specific T cells in the lymph node

Summary

Introduction

Dendritic cells (DCs) in the skin and mucosa play a major role as sentinels in the detection and uptake of pathogens and initiation of innate and adaptive immune responses [1]. Herpes Simplex Virus (HSV) types 1 and 2 are examples of closely related pathogens which invade the anogenital mucosa, penetrating into the stratified squamous epithelium especially where the overlaying stratum corneum is thin, absent or traumatically destroyed [2]. Primary or initial genital herpes is defined as the first episode of herpetic lesions (HSV types 1 or 2) without pre-existing antibodies. As recognized in patients with severe immunosuppression [9, 10], T cells play a major role in the control of both initial and recurrent herpes simplex [11]

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