Cutting Edge: Langerin/CD207 Receptor on Dendritic Cells Mediates Efficient Antigen Presentation on MHC I and II Products In Vivo

Idoyaga, Juliana; Cheong, Cheolho; Suda, K.; Suda, Nao; Kim, Jae Y.; Lee, Haekyung; Park, Chae Gyu; Steinman, Ralph M.

doi:10.4049/jimmunol.180.6.3647

Cited by 146 publications

(161 citation statements)

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“…In other studies, C-type lectin activation resulted in the secretion of multiple cytokines and chemokines by DCs [32,34,35], even if the upregulation of costimulatory molecules was not always detected. Moreover, C-type lectin targeting increased DC cross-presentation or improved the activation by DCs of specific lymphocyte subsets [36,37].In our system the engagement of MGL by both ligands induced activation of antigen-specific CD8 + T cells as detected by IFN-γ production, while only DCs stimulated with the antibody, induced the proliferation of allogeneic T cells similarly to mDCs. The difference in the profile of costimulatory molecules observed could make account for the distinct immunogenicity.…”

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confidence: 78%

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Targeting of macrophage galactose‐type C‐type lectin (MGL) induces DC signaling and activation

et al. 2012

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Dendritic cells (DCs) sense the microenvironment through several types of receptors recognizing pathogen-associated molecular patterns. In particular, C-type lectins, expressed by distinct subsets of DCs, recognize and internalize specific carbohydrate antigen in a Ca 2+ -dependent manner. Targeting of these receptors is becoming an efficient strategy of delivering antigens in DC-based anticancer immunotherapy. Here we investigated the role of the macrophage galactose type C-lectin receptor (MGL), expressed by immature DCs (iDCs), as a molecular target for α-N-acetylgalactosamine (GalNAc or Tn)-carrying tumor-associated antigens to improve DC performance. MGL expressed by ex vivo-generated iDCs from healthy donors was engaged by a 60-mer MUC1 9Tn -glycopeptide as a Tn-carrying tumor-associated antigen, and an anti-MGL antibody, as a specific MGL binder. We demonstrated that MGL engagement induced homotrimers and homodimers, triggering the phosphorylation of extracellular signal-regulated kinase 1,2 (ERK1,2) and nuclear factor-κB activation. Analysis of DC phenotype and function demonstrated that MGL engagement improved DC performance as antigen-presenting cells, promoting the upregulation of maturation markers, a decrease in phagocytosis, an enhancement of motility, and most importantly an increase in antigen-specific CD8 + T-cell activation. These results demonstrate that the targeting of MGL receptor on human DCs has an adjuvant effect and that this strategy can be used to design novel anticancer vaccines. Keywords: C-type lectins · Dendritic cells · Macrophage galactose-type C-type lectin (MGL) · MUC1 · Tn-tumor associated antigens IntroductionDendritic cells (DCs), as professional antigen-presenting cells (APCs), sense the microenvironment through different types of Correspondence: Prof. Marianna Nuti e-mail: marianna.nuti@uniroma1.it receptors to scan local environmental changes and eliminate incoming pathogens [1]. They play an essential role in the uptake of self-or pathogen-associated antigens, thus, steering and directing the immune response. After activation, DCs migrate to the draining lymph nodes, where they initiate specific immunity * These authors contributed equally to this work. The most important molecules from the CLR family include macrophage galactose type C-lectin (MGL), dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin (DC-SIGN), the mannose receptor, DEC205, and Dectin-1. These receptors are able to trigger distinct signaling pathways that modulate DC functions through the expression of specific molecules and cytokines, determining the polarization of T cells [4]. These properties make this C-type lectin family an optimal tool for DC targeting in cancer vaccination. Human MGL (hMGL) is a type II C-type lectin, expressed in vitro by macrophages and monocyte derived DCs and in vivo by DCs of skin and lymph nodes [5,6]. Its carbohydrate recognition domains contain a QPD sequence that is responsible for recognition of α-or β-N-acetylgalactosamine (GalNAc, Tn) res...

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Targeting of macrophage galactose‐type C‐type lectin (MGL) induces DC signaling and activation

et al. 2012

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“…Different studies have suggested a balance between efficient targeting of antigens for presentation in HLA-I or HLA-II [4,15,42]. Langerin internalizes antigens into Birbeck granules that might prevent antigens from entering the cross-presentation route or prevent triggering of pattern recognition receptors that could be required for cross-presentation [43].…”

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confidence: 99%

“…Furthermore, MV-infected mature LCs are capable of presenting endogenous MV antigens in the context of HLA-I molecules. Taken together these results strongly suggest that capture of MV by primary LCs results in presentation of antigens in the context of HLA-II molecules, but does not lead to cross-presentation of MV to CD8 1 T cells.Different studies have suggested a balance between efficient targeting of antigens for presentation in HLA-I or HLA-II [4,15,42]. Langerin internalizes antigens into Birbeck granules that might prevent antigens from entering the cross-presentation route or prevent triggering of pattern recognition receptors that could be required for cross-presentation [43].…”

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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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Cellular Immunity of the Skin: Langerhans Cells and Dendritic Cells

Burke

Anandasabapathy

2011

Innate Immune System of Skin and Oral Mucosa

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Cutting Edge: Langerin/CD207 Receptor on Dendritic Cells Mediates Efficient Antigen Presentation on MHC I and II Products In Vivo

Cited by 146 publications

References 19 publications

Targeting of macrophage galactose‐type C‐type lectin (MGL) induces DC signaling and activation

Targeting of macrophage galactose‐type C‐type lectin (MGL) induces DC signaling and activation

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

Cellular Immunity of the Skin: Langerhans Cells and Dendritic Cells

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Cutting Edge: Langerin/CD207 Receptor on Dendritic Cells Mediates Efficient Antigen Presentation on MHC I and II Products In Vivo

Cited by 146 publications

References 19 publications

Targeting of macrophage galactose‐type C‐type lectin (MGL) induces DC signaling and activation

Targeting of macrophage galactose‐type C‐type lectin (MGL) induces DC signaling and activation

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

Cellular Immunity of the Skin: Langerhans Cells and Dendritic Cells

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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