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

Abstract

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...

The Macrophage Galactose-Type Lectin Can Function as an Attachment and Entry Receptor for Influenza Virus

“…The particular receptors engaged by IAV are likely to determine selection of particular endocytic pathways. Experimental cell culture conditions also modulate endocytic pathways (49)(50)(51)(52)(53), and addition of serum was shown to induce dynamin-independent macropinocytosis as an alternative IAV entry pathway in addition to CME (5,54). Compared to spherical virions, filamentous IAV use macropinocytosis as the primary mechanism of virus entry, likely avoiding the size restriction of clathrincoated vesicles (6).…”

The C-type Lectin Langerin Functions as a Receptor for Attachment and Infectious Entry of Influenza A Virus

“…Birbeck granules are cytoplasmic organelles present in Langerhans cells but can be induced by ectopic expression of langerin in heterologous cells (13,27). The function of Birbeck granules is still not clear, although most studies suggest an active role in receptormediated endocytosis, intracellular trafficking, and/or processing and presentation of antigen (63,67).…”

“…While apparent contradictions have been reported regarding the role of langerin in HIV-1 infection, these likely reflect differences in the cell models used, the isolation methods and maturation status of primary cells, and the titers of inoculum used (20,24). In addition to interactions with HIV-1, langerin has been reported to bind to herpes simplex virus 2 (26) and langerin-mediated capture of measles virus has been implicated in contributing to the processing and presentation of antigen to virus-specific CD4 ϩ T cells (27). Human langerin is expressed primarily by Langerhans cells (28), which in the airways tend to be present at a higher frequency in the epidermis and epithelia of the upper respiratory tract than in the lung (27).…”

“…In addition to interactions with HIV-1, langerin has been reported to bind to herpes simplex virus 2 (26) and langerin-mediated capture of measles virus has been implicated in contributing to the processing and presentation of antigen to virus-specific CD4 ϩ T cells (27). Human langerin is expressed primarily by Langerhans cells (28), which in the airways tend to be present at a higher frequency in the epidermis and epithelia of the upper respiratory tract than in the lung (27). Murine langerin is also expressed by some DC subsets, including mucosal CD11b Ϫ CD103 ϩ DC in the lungs, a population that can migrate to draining lymph nodes following IAV infection (29,30).…”

Measles Virus Transmission from Dendritic Cells to T Cells: Formation of Synapse-Like Interfaces Concentrating Viral and Cellular Components

“…In common with HIV, MV is captured by C-type lectin receptors such as Langerin or DC-SIGN on Langerhans cells (LCs) or DCs (7). While LCs barely support cis-infection by MV, which is instead sorted to Birbeck granules (48), MV enters into and replicates in myeloid DCs, and this is dependent on the expression of CD150, the MV entry receptor on hematopoietic cells in vitro and in vivo (4)(5)(6)(7)(8)50). Because DC-SIGN ϩ cells with DC morphology did not detectably display CD150 on their surfaces in healthy deep respiratory tract tissues, these cells were considered as primarily capturing MV via DC-SIGN and, thus, MV transmission to T cells would mainly occur by trans-infection (8).…”