Langerhans cells cross-present antigen derived from skin

Stoitzner, Patrizia; Tripp, Christoph H.; Eberhart, Andreas; Price, Kylie M.; Jung, Ji Ye; Bursch, Laura S.; Ronchese, Franca; Romani, Nikolaus

doi:10.1073/pnas.0509307103

Cited by 181 publications

(172 citation statements)

References 47 publications

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“…Murine myeloid DCs cross-present viral antigens and induce anti-viral CD8 1 T cells [37]. Murine LCs were reported to cross-present antigens [14] although a role for Langerin 1 dermal DCs was not excluded. More recently, in vivo studies indicate that murine Langerin 1 dermal DCs, but not LCs, are responsible for the induction of CD8 1 T-cell responses [38,39].…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2011

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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...

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Section: Discussionmentioning

confidence: 99%

“…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.…”

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confidence: 99%

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

et al. 2011

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“…Indeed, they have been shown to take up skin Ags and migrate to the skin draining lymph nodes (2) where they can potentially interact with T cells. Based primarily on in vitro studies, it is envisaged that LCs undergo a process of maturation coordinate with migration, where they upregulate MHC, costimulatory, and adhesion molecules, and act as potent stimulators of naive CD4 and CD8 T cells when they arrive in the lymph node (3)(4)(5). Indeed, epicutaneous immunization strategies, which are presumed to involve LC, are effective at inducing functional CTL (6,7) and have led to clinical trials with positive preliminary findings for influenza and travelers' diarrhea (www.iomai.com) (8,9).…”

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confidence: 99%

Langerin Expressing Cells Promote Skin Immune Responses under Defined Conditions

Wang

Bursch

Kissenpfennig

et al. 2008

The Journal of Immunology

106

102

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There are conflicting data in the literature regarding the role of epidermal Langerhans cells (LC) in promoting skin immune responses. On one hand, LC can be extremely potent APCs in vitro, and are thought to be involved in contact hypersensitivity (CHS). On the other hand, it seems counterintuitive that a cell type continually exposed to pathogens at the organism’s barrier surfaces should readily trigger potent T cell responses. Indeed, LC depletion in one model led to enhanced contact hypersensitivity, suggesting they play a negative regulatory role. However, apparently similar LC depletion models did not show enhanced CHS, and in one case showed reduced CHS. In this study we found that acute depletion of mouse LC reduced CHS, but the timing of toxin administration was critical: toxin administration 3 days before priming did not impair CHS, whereas toxin administration 1 day before priming did. We also show that LC elimination reduced the T cell response to epicutaneous immunization with OVA protein Ag. However, this reduction was only observed when OVA was applied on the flank skin, and not on the ear. Additionally, peptide immunization was not blocked by depletion, regardless of the site. Finally we show that conditions which eliminate epidermal LC but spare other Langerin+ DC do not impair the epicutaneous immunization response to OVA. Overall, our results reconcile previous conflicting data in the literature, and suggest that Langerin+ cells do promote T cell responses to skin Ags, but only under defined conditions.

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“…We reported recently that Langerhans cells isolated from epidermis or emigrated from skin explants cross-presented soluble protein or cell-associated antigen on MHC-class I molecules to CD8 + T cells. Activated CD8 + T cells produced IFN-upon restimulation and exerted cytotoxic activity [53].…”

Section: Langerhans Cell Functions Relevant To Cancer Immunotherapy: mentioning

confidence: 99%

“…We demonstrated recently that Langerhans cells capture exogenous skin-derived antigen, process it and cross-present antigenic peptides on MHC-class I to CD8 + T cells in vitro and in vivo [53]. Langerhans cells thus represent a major subset of skin dendritic cells that, together with dermal dendritic cells, are equipped to fulWll the task of surveying skin for invading pathogens and stimulating immune responses against skin-borne pathogens [43].…”

Section: Functions Of Langerhans Cellsmentioning

confidence: 99%

Targeting of epidermal Langerhans cells with antigenic proteins: attempts to harness their properties for immunotherapy

Flacher

Sparber

Tripp

et al. 2008

Cancer Immunol Immunother

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Langerhans cells, a subset of skin dendritic cells in the epidermis, survey peripheral tissue for invading pathogens. In recent functional studies it was proven that Langerhans cells can present exogenous antigen not merely on major histocompatibility complexes (MHC)-class II molecules to CD4 + T cells, but also on MHC-class I molecules to CD8 + T cells. Immune responses against topically applied antigen could be measured in skin-draining lymph nodes. Skin barrier disruption or co-application of adjuvants was required for maximal induction of T cell responses. Cytotoxic T cells induced by topically applied antigen inhibited tumor growth in vivo, thus underlining the potential of Langerhans cells for immunotherapy. Here we review recent work and report novel observations relating to the potential use of Langerhans cells for immunotherapy. We investigated the potential of epicutaneous immunization strategies in which resident skin dendritic cells are loaded with tumor antigen in situ. This contrasts with current clinical approaches, where dendritic cells generated from progenitors in blood are loaded with tumor antigen ex vivo before injection into cancer patients. In the current study, we applied either Xuorescently labeled protein antigen or targeting antibodies against DEC-205/ CD205 and langerin/CD207 topically onto barrier-disrupted skin and examined antigen capture and transport by Langerhans cells. Protein antigen could be detected in Langerhans cells in situ, and they were the main skin dendritic cell subset transporting antigen during emigration from skin explants. Potent in vivo proliferative responses of CD4 + and CD8 + T cells were measured after epicutaneous immunization with low amounts of protein antigen. Targeting antibodies were mainly transported by langerin + migratory dendritic cells of which the majority represented migratory Langerhans cells and a smaller subset the new langerin + dermal dendritic cell population located in the upper dermis. The preferential capture of topically applied antigen by Langerhans cells and their ability to induce potent CD4 + and CD8 + T cell responses emphasizes their potential for epicutaneous immunization strategies.

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Langerhans cells cross-present antigen derived from skin

Abstract: cross-presentation ͉ dendritic cells ͉ epidermis ͉ mouse or murine ͉ epicutaneous

Cited by 181 publications

References 47 publications

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

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

Langerin Expressing Cells Promote Skin Immune Responses under Defined Conditions

Targeting of epidermal Langerhans cells with antigenic proteins: attempts to harness their properties for immunotherapy

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Langerhans cells cross-present antigen derived from skin

Abstract: cross-presentation ͉ dendritic cells ͉ epidermis ͉ mouse or murine ͉ epicutaneous

Cited by 181 publications

References 47 publications

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

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

Langerin Expressing Cells Promote Skin Immune Responses under Defined Conditions

Targeting of epidermal Langerhans cells with antigenic proteins: attempts to harness their properties for immunotherapy

Contact Info

Product

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

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