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.

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Ixodes ticks are major vectors for human pathogens, such as Borrelia burgdorferi, the causative agent of Lyme disease. Tick saliva contains immunosuppressive molecules that facilitate tick feeding and B. burgdorferi infection. We here demonstrate, to our knowledge for the first time, that the Ixodes scapularis salivary protein Salp15 inhibits adaptive immune responses by suppressing human dendritic cell (DC) functions. Salp15 inhibits both Toll-like receptor- and B. burgdorferi–induced production of pro-inflammatory cytokines by DCs and DC-induced T cell activation. Salp15 interacts with DC-SIGN on DCs, which results in activation of the serine/threonine kinase Raf-1. Strikingly, Raf-1 activation by Salp15 leads to mitogen-activated protein kinase kinase (MEK)-dependent decrease of IL-6 and TNF-α mRNA stability and impaired nucleosome remodeling at the IL-12p35 promoter. These data demonstrate that Salp15 binding to DC-SIGN triggers a novel Raf-1/MEK-dependent signaling pathway acting at both cytokine transcriptional and post-transcriptional level to modulate Toll-like receptor–induced DC activation, which might be instrumental to tick feeding and B. burgdorferi infection, and an important factor in the pathogenesis of Lyme disease. Insight into the molecular mechanism of immunosuppression by tick salivary proteins might provide innovative strategies to combat Lyme disease and could lead to the development of novel anti-inflammatory or immunosuppressive agents.

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Langerhans cells (LCs) lining the stratified epithelia and mucosal tissues are the first antigen presenting cells to encounter invading pathogens, such as viruses, bacteria and fungi. Fungal infections form a health threat especially in immuno-compromised individuals. LCs express C-type lectin Langerin that has specificity for mannose, fucose and GlcNAc structures. Little is known about the role of human Langerin in fungal infections. Our data show that Langerin interacts with both mannan and β-glucan structures, common cell-wall carbohydrate structures of fungi. We have screened a large panel of fungi for recognition by human Langerin and, strikingly, we observed strong binding of Langerin to a variety of Candida and Saccharomyces species and Malassezia furfur, but very weak binding was observed to Cryptococcus gattii and Cryptococcus neoformans. Notably, Langerin is the primary fungal receptor on LCs, since the interaction of LCs with the different fungi was blocked by antibodies against Langerin. Langerin recognizes both mannose and β-glucans present on fungal cell walls and our data demonstrate that Langerin is the major fungal pathogen receptor on human LCs that recognizes pathogenic and commensal fungi. Together these data may provide more insight in the role of LCs in fungal infections.

Langerhans cells (LCs) are a subset of DCs that reside in the upper respiratory tract and are ideally suited to sense respiratory virus infections. Measles virus (MV) is a highly infectious lymphotropic and myelotropic virus that enters the host via the respiratory tract. Here, we show that human primary LCs are capable of capturing MV through the C-type lectin Langerin. Both immature and mature LCs presented MV-derived antigens in the context of HLA class II to MV-specific CD4 1 T cells. Immature LCs were not susceptible to productive infection by MV and did not present endogenous viral antigens in the context of HLA class I. In contrast, mature LCs could be infected by MV and presented de novo synthesized viral antigens to MV-specific CD8 1 T cells. Notably, neither immature nor mature LCs were able to cross-present exogenous UV-inactivated MV or MV-infected apoptotic cells. The lack of direct infection of immature LCs, and the inability of both immature and mature LCs to crosspresent MV antigens, suggest that human LCs may not be directly involved in priming MV-specific CD8 1 T cells. Immune activation of LCs seems a prerequisite for MV infection of LCs and subsequent CD8 1 T-cell priming via the endogenous antigen presentation pathway. Eur. J. Immunol. 2011. 41: 2619-2631 DOI 10.1002 Immunity to infection 2619 molecules, a process referred to as cross-presentation which is thought to be important in both viral and tumor immunity [2,3]. It is becoming evident that different DC subsets have specialized functions in anti-viral immunity, e.g. by inducing preferentially CD4 1 or CD8 1 T-cell responses or by inducing innate immunity against pathogens [4,5]. Langerhans cells (LCs) are a subset of DCs that are, in humans, characterized by expression of CD1a, the C-type lectin Langerin and the presence of Birbeck granules [6]. 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.Capture of exogenous antigens by LCs leads to induction of CD4 1 T-cell responses [11][12][13]. However, the ability of LCs to cross-present exogenous antigens to CD8 1 T cells has been debated [14][15][16][17]. Klechevsky et al. [13] have shown that in vitrogenerated human LCs from either CD34 1 cells or monocytes are capable of cross-presenting influenza-virus proteins to CD8 1 T cells. However, these in vitro-generated LCs might be different from primary immature LCs.Here, we have investigated the antigen capture and presentation capacity of human primary LCs during measles virus (MV) infection. MV is the causative agent of measles, which remains an important cause of morbidity and mortality in developing countries. MV is a lymphotropic and myelotropic virus and DCs have been implicated in its transmission [18,19]. MV is on...

Dendritic cells (DCs) orchestrate antibody-mediated responses to combat extracellular pathogens including parasites by initiating T helper cell differentiation. Here we demonstrate that carbohydrate-specific signalling by DC-SIGN drives follicular T helper cell (T FH ) differentiation via IL-27 expression. Fucose, but not mannose, engagement of DC-SIGN results in activation of IKKe, which collaborates with type I IFNR signalling to induce formation and activation of transcription factor ISGF3. Notably, ISGF3 induces expression of IL-27 subunit p28, and subsequent IL-27 secreted by DC-SIGN-primed DCs is pivotal for the induction of Bcl-6 þ CXCR5 þ PD-1 hi Foxp1 lo T FH cells, IL-21 secretion by T FH cells and T-cell-dependent IgG production by B cells. Thus, we have identified an essential role for DC-SIGN-induced ISGF3 by fucose-based PAMPs in driving IL-27 and subsequent T FH polarization, which might be harnessed for vaccination design.

Genital herpes is the most prevalent viral sexually transmitted infection worldwide and is mainly caused by HSV type 2 (HSV-2). HSV-2 infection enhances HIV-1 susceptibility, even in the absence of clinical symptoms. In this study, we investigated the effect of HSV-2 on HIV-1 transmission by mucosal Langerhans cells (LCs). LCs are important in heterosexual transmission because they form a barrier against HIV-1 infection; LCs efficiently capture and degrade HIV-1 through the C-type lectin langerin, thereby preventing HIV-1 transmission. Notably, our data showed that HSV-2 enhanced HIV-1 infection of LCs and subsequent HIV-1 transmission to T cells. HSV-2 interfered with HIV-1 capture by langerin, which allowed efficient HIV-1 infection of LCs. HSV-2 inhibited the antiviral function of langerin at two levels; HSV-2 decreased langerin expression and competed with HIV-1 for langerin binding. HSV-2 replication was not required, because both UV-inactivated HSV-2 and TLR-3 agonist polyinosinic:polycytidylic acid similarly increased HIV-1 transmission by LCs. Therefore, we identified a mechanism by which HSV-2 enhances HIV-1 susceptibility, even in the absence of clinical symptoms. Our data demonstrated that viral coinfections, such as HSV-2, breach the protective function of LCs by abrogating langerin function, which increases HIV-1 susceptibility. These data reinforce the importance of preventing sexually transmitted infections, such as HSV-2, to reduce the transmission of HIV-1.