Langerin is a natural barrier to HIV-1 transmission by Langerhans cells

Abstract

Human immunodeficiency virus-1 (HIV-1) is primarily transmitted sexually. Dendritic cells (DCs) in the subepithelium transmit HIV-1 to T cells through the C-type lectin DC-specific intercellular adhesion molecule (ICAM)-3-grabbing nonintegrin (DC-SIGN). However, the epithelial Langerhans cells (LCs) are the first DC subset to encounter HIV-1. It has generally been assumed that LCs mediate the transmission of HIV-1 to T cells through the C-type lectin Langerin, similarly to transmission by DC-SIGN on dendritic cells (DCs). Here we show that in stark contrast to DC-SIGN, Langerin prevents HIV-1 transmission by LCs. HIV-1 captured by Langerin was internalized into Birbeck granules and degraded. Langerin inhibited LC infection and this mechanism kept LCs refractory to HIV-1 transmission; inhibition of Langerin allowed LC infection and subsequent HIV-1 transmission. Notably, LCs also inhibited T-cell infection by viral clearance through Langerin. Thus Langerin is a natural barrier to HIV-1 infection, and strategies to combat infection must enhance, preserve or, at the very least, not interfere with Langerin expression and function.

Human Langerhans cells capture measles virus through Langerin and present viral antigens to CD4+ T cells but are incapable of cross‐presentation

“…Cryosections were immuno-labeled with anti-mouse antibodies (15 nm protein A gold label) to detect bound and internalized DCGM4 and either one of the following antibodies: goat anti-Langerin, anti-Lamp-1, rabbit anti-HLA-DR (10 nm protein A gold label) and analyzed as described before [10].…”

“…LCs reside in the epidermis and stratified epithelial tissues [7][8][9]. Recently, we have shown that LCs form a barrier against HIV-1; LCs capture HIV-1 through Langerin, resulting in internalization of HIV-1 into Birbeck granules and preventing subsequent HIV-1 transmission [10]. However, little is known about the role of human LCs and Langerin in antigen presentation.…”

Langerhans cells and viral immunity

“…LC may also provide a mode of intracellular storage while transporting HIV to CD4 lymphocytes in the submucosal lymphoid tissue and thence to draining lymph nodes [16]. Recent data suggest that LC may have an anti-viral function by capturing HIV-1 for degradation and thus initially impairing HIV-1 transmission [25]. This antiviral function is dependent on viral load and LC phenotype, strongly suggesting that the role of LC in HIV-1 transmission is also likely to be influenced by local conditions such as viral load, stage of the menstrual cycle, state of vaginal mucus and/or inflammation and co-infections.…”

“…Recent data suggest that the CLR Langerin on LC captures HIV-1 for internalisation into LC-specific vesicular organelle Birbeck granules for degradation, thereby preventing cis-transfer to CD4/CCR5, thus differing from DC-SIGN on monocyte-derived DC. Thus, Langerin binding effectively inhibited de novo infection of LC and subsequent transfer to CD4 lymphocytes, an effect which could be overcome by inhibition of Langerin or by high concentrations of HIV which saturated Langerin function [25]. The critical role of LC in anti-viral defence can explain differences in HIV-1 susceptibility, as the risk of acquiring HIV-1 is severely increased by inflammation, ulceration and co-infection with sexually transmitted diseases.…”

“…Such DC more closely resemble lamina propria DC, particularly in the types of CLR expressed in the endocervix. Although similar mechanisms were assumed to be involved in LC transmission of HIV-1, it is becoming evident that LC might have a more complicated role in transmission [25]. Monocyte-derived DC capture HIV through the CLR DC-SIGN [26] and, to lesser degrees, mannose receptor and heparin sulphate proteoglycan syndecan-3 [27].…”