Mairhofer David G, Ortner Daniela, Tripp Christoph H, Schaffenrath Sandra, Fleming Viktor, Heger Lukas, Komenda Kerstin, Reider Daniela, Dudziak Diana, Chen Suzie, Becker Jürgen C, Flacher Vincent, Stoitzner Patrizia
Impaired gp100-Specific CD8(+) Ŧ-Cell Responses in the Presence of Myeloid-Derived Suppressor Cells in a Spontaneous Mouse Melanoma Model Journal Article
In: The Journal of Investigative Dermatology, vol. 135, no. 11, pp. 2785–2793, 2015, ISSN: 1523-1747.
Abstract | Links | BibTeX | Tags: Analysis of Variance, Animal, Animals, Antigen, cancer, CARCINOGENESIS, CD8-Positive T-Lymphocytes, Cell Proliferation, Cultured, DERMATOLOGY, development, disease, Disease Models, Experimental, GLYCOPROTEIN, gp100 Melanoma Antigen, Growth, Human, Humans, Immunity, Immunologic, IN VITRO, Inbred C57BL, iNOS, Leukocytes, LYMPH, LYMPH NODE, Lymph Nodes, Lymphocyte Activation, MELANOCYTES, Melanoma, Mice, mouse, murine, NITRIC OXIDE, nitric oxide synthase, Phenotype, Proliferation, Random Allocation, Receptor, Regulatory, RESPONSES, Skin, SUBSETS, Suppressor Factors, T CELLS, T-CELLS, T-Lymphocytes, Team-Mueller, Transforming Growth Factor beta, transgenic, tumor, Tumor Cells, tumor immunity
@article{mairhofer_impaired_2015,
title = {Impaired gp100-Specific CD8(+) Ŧ-Cell Responses in the Presence of Myeloid-Derived Suppressor Cells in a Spontaneous Mouse Melanoma Model},
author = {David G Mairhofer and Daniela Ortner and Christoph H Tripp and Sandra Schaffenrath and Viktor Fleming and Lukas Heger and Kerstin Komenda and Daniela Reider and Diana Dudziak and Suzie Chen and Jürgen C Becker and Vincent Flacher and Patrizia Stoitzner},
doi = {10.1038/jid.2015.241},
issn = {1523-1747},
year = {2015},
date = {2015-11-01},
journal = {The Journal of Investigative Dermatology},
volume = {135},
number = {11},
pages = {2785--2793},
abstract = {Murine tumor models that closely reflect human diseases are important tools to investigate carcinogenesis and tumor immunity. The transgenic (tg) mouse strain tg(Grm1)EPv develops spontaneous melanoma due to ectopic overexpression of the metabotropic glutamate receptor 1 (Grm1) in melanocytes. In the present study, we characterized the immune status and functional properties of immune cells in tumor-bearing mice. Melanoma development was accompanied by a reduction in the percentages of CD4(+) T cells including regulatory T cells (Tregs) in CD45(+) leukocytes present in tumor tissue and draining lymph nodes (LNs). In contrast, the percentages of CD8(+) T cells were unchanged, and these cells showed an activated phenotype in tumor mice. Endogenous melanoma-associated antigen glycoprotein 100 (gp100)-specific CD8(+) T cells were not deleted during tumor development, as revealed by pentamer staining in the skin and draining LNs. They, however, were unresponsive to ex vivo gp100-peptide stimulation in late-stage tumor mice. Interestingly, immunosuppressive myeloid-derived suppressor cells (MDSCs) were recruited to tumor tissue with a preferential accumulation of granulocytic MDSC (grMDSCs) over monocytic MDSC (moMDSCs). Both subsets produced Arginase-1, inducible nitric oxide synthase (iNOS), and transforming growth factor-β and suppressed T-cell proliferation in vitro. In this work, we describe the immune status of a spontaneous melanoma mouse model that provides an interesting tool to develop future immunotherapeutical strategies.},
keywords = {Analysis of Variance, Animal, Animals, Antigen, cancer, CARCINOGENESIS, CD8-Positive T-Lymphocytes, Cell Proliferation, Cultured, DERMATOLOGY, development, disease, Disease Models, Experimental, GLYCOPROTEIN, gp100 Melanoma Antigen, Growth, Human, Humans, Immunity, Immunologic, IN VITRO, Inbred C57BL, iNOS, Leukocytes, LYMPH, LYMPH NODE, Lymph Nodes, Lymphocyte Activation, MELANOCYTES, Melanoma, Mice, mouse, murine, NITRIC OXIDE, nitric oxide synthase, Phenotype, Proliferation, Random Allocation, Receptor, Regulatory, RESPONSES, Skin, SUBSETS, Suppressor Factors, T CELLS, T-CELLS, T-Lymphocytes, Team-Mueller, Transforming Growth Factor beta, transgenic, tumor, Tumor Cells, tumor immunity},
pubstate = {published},
tppubtype = {article}
}
Flacher Vincent, Tripp Christoph H, Mairhofer David G, Steinman Ralph M, Stoitzner Patrizia, Idoyaga Juliana, Romani Nikolaus
Murine Langerin+ dermal dendritic cells prime CD8+ Ŧ cells while Langerhans cells induce cross-tolerance Journal Article
In: EMBO molecular medicine, vol. 6, no. 9, pp. 1191–1204, 2014, ISSN: 1757-4684.
Abstract | Links | BibTeX | Tags: agonists, Animals, Antibodies, antibody, Antigen, Antigen Presentation, Antigens, C-Type, C-type lectin, cancer, CD70, CD8-Positive T-Lymphocytes, CD8+ T cells, CD8+ T‐cell responses, Cellular, CROSS-PRESENTATION, Cross-Priming, Cytotoxicity, Dendritic Cells, DERMAL DENDRITIC CELLS, DERMATOLOGY, disease, imiquimod, Immunization, IMMUNOGENICITY, Immunologic Memory, Immunological, Immunology, In vivo, Inbred C57BL, INDUCTION, Intradermal, Langerhans Cells, LECTIN, Lectins, Mannose-Binding Lectins, Maturation, Mice, Models, murine, OVALBUMIN, physiology, priming, RESPONSES, Skin, Surface, T CELLS, T-CELLS, Team-Mueller, tolerance, Vaccination, vaccine, Vaccines
@article{flacher_murine_2014,
title = {Murine Langerin+ dermal dendritic cells prime CD8+ Ŧ cells while Langerhans cells induce cross-tolerance},
author = {Vincent Flacher and Christoph H Tripp and David G Mairhofer and Ralph M Steinman and Patrizia Stoitzner and Juliana Idoyaga and Nikolaus Romani},
doi = {10.15252/emmm.201303283},
issn = {1757-4684},
year = {2014},
date = {2014-09-01},
journal = {EMBO molecular medicine},
volume = {6},
number = {9},
pages = {1191--1204},
abstract = {Skin dendritic cells (DCs) control the immunogenicity of cutaneously administered vaccines. Antigens targeted to DCs via the C-type lectin Langerin/CD207 are cross-presented to CD8(+) T cells in vivo. We investigated the relative roles of Langerhans cells (LCs) and Langerin(+) dermal DCs (dDCs) in different vaccination settings. Poly(I:C) and anti-CD40 agonist antibody promoted cytotoxic responses upon intradermal immunization with ovalbumin (OVA)-coupled anti-Langerin antibodies (Langerin/OVA). This correlated with CD70 upregulation in Langerin(+) dDCs, but not LCs. In chimeric mice where Langerin targeting was restricted to dDCs, CD8(+) T-cell memory was enhanced. Conversely, providing Langerin/OVA exclusively to LCs failed to prime cytotoxicity, despite initial antigen cross-presentation to CD8(+) T cells. Langerin/OVA combined with imiquimod could not prime CD8(+) T cells and resulted in poor cytotoxicity in subsequent responses. This tolerance induction required targeting and maturation of LCs. Altogether, Langerin(+) dDCs prime long-lasting cytotoxic responses, while cross-presentation by LCs negatively influences CD8(+) T-cell priming. Moreover, this highlights that DCs exposed to TLR agonists can still induce tolerance and supports the existence of qualitatively different DC maturation programs.},
keywords = {agonists, Animals, Antibodies, antibody, Antigen, Antigen Presentation, Antigens, C-Type, C-type lectin, cancer, CD70, CD8-Positive T-Lymphocytes, CD8+ T cells, CD8+ T‐cell responses, Cellular, CROSS-PRESENTATION, Cross-Priming, Cytotoxicity, Dendritic Cells, DERMAL DENDRITIC CELLS, DERMATOLOGY, disease, imiquimod, Immunization, IMMUNOGENICITY, Immunologic Memory, Immunological, Immunology, In vivo, Inbred C57BL, INDUCTION, Intradermal, Langerhans Cells, LECTIN, Lectins, Mannose-Binding Lectins, Maturation, Mice, Models, murine, OVALBUMIN, physiology, priming, RESPONSES, Skin, Surface, T CELLS, T-CELLS, Team-Mueller, tolerance, Vaccination, vaccine, Vaccines},
pubstate = {published},
tppubtype = {article}
}
Flacher V, Tripp C H, Haid B, Kissenpfennig A, Malissen B, Stoitzner P, Idoyaga J, Romani N
Skin langerin+ dendritic cells transport intradermally injected anti-DEC-205 antibodies but are not essential for subsequent cytotoxic CD8+ Ŧ cell responses Journal Article
In: Journal of Immunology, vol. 188, no. 1550-6606 (Electronic), pp. 2146–2155, 2012.
Abstract | BibTeX | Tags: administration & dosage, Animals, Antibodies, antibody, Antigen, Antigens, Biosynthesis, C-Type, C-type lectin, CD, Cell Surface, Comparative Study, Cytotoxic, Dendritic Cells, DERMATOLOGY, Gene Knock-In Techniques, Genetics, imiquimod, immune response, IMMUNE-RESPONSES, Immunization, Immunology, in situ, In vivo, Inbred BALB C, Inbred C57BL, INDUCTION, inflammation, Inflammation Mediators, Injections, Intradermal, knock-in, Langerhans Cells, LECTIN, Lectins, LYMPH, LYMPH NODE, Lymph Nodes, LYMPHATIC VESSEL, Lymphatic Vessels, mAb, Mannose-Binding Lectins, MEDIATOR, metabolism, Mice, Minor Histocompatibility Antigens, mouse, murine, Organ Culture Techniques, Ovum, pathology, physiology, Protein, Protein Transport, Rats, Receptor, Receptors, RESPONSES, Skin, SUBSETS, Surface, T-Lymphocytes, target, Team-Mueller, TLR7, transgenic
@article{flacher_skin_2012,
title = {Skin langerin+ dendritic cells transport intradermally injected anti-DEC-205 antibodies but are not essential for subsequent cytotoxic CD8+ Ŧ cell responses},
author = {V Flacher and C H Tripp and B Haid and A Kissenpfennig and B Malissen and P Stoitzner and J Idoyaga and N Romani},
year = {2012},
date = {2012-03-01},
journal = {Journal of Immunology},
volume = {188},
number = {1550-6606 (Electronic)},
pages = {2146--2155},
abstract = {Incorporation of Ags by dendritic cells (DCs) increases when Ags are targeted to endocytic receptors by mAbs. We have previously demonstrated in the mouse that mAbs against C-type lectins administered intradermally are taken up by epidermal Langerhans cells (LCs), dermal Langerin(neg) DCs, and dermal Langerin(+) DCs in situ. However, the relative contribution of these skin DC subsets to the induction of immune responses after Ag targeting has not been addressed in vivo. We show in this study that murine epidermal LCs and dermal DCs transport intradermally injected mAbs against the lectin receptor DEC-205/CD205 in vivo. Skin DCs targeted in situ with mAbs migrated through lymphatic vessels in steady state and inflammation. In the skin-draining lymph nodes, targeting mAbs were found in resident CD8alpha(+) DCs and in migrating skin DCs. More than 70% of targeted DCs expressed Langerin, including dermal Langerin(+) DCs and LCs. Numbers of targeted skin DCs in the nodes increased 2-3-fold when skin was topically inflamed by the TLR7 agonist imiquimod. Complete removal of the site where OVA-coupled anti-DEC-205 had been injected decreased endogenous cytotoxic responses against OVA peptide-loaded target cells by 40-50%. Surprisingly, selective ablation of all Langerin(+) skin DCs in Langerin-DTR knock-in mice did not affect such responses independently of the adjuvant chosen. Thus, in cutaneous immunization strategies where Ag is targeted to DCs, Langerin(+) skin DCs play a major role in transport of anti-DEC-205 mAb, although Langerin(neg) dermal DCs and CD8alpha(+) DCs are sufficient to subsequent CD8(+) T cell responses},
keywords = {administration & dosage, Animals, Antibodies, antibody, Antigen, Antigens, Biosynthesis, C-Type, C-type lectin, CD, Cell Surface, Comparative Study, Cytotoxic, Dendritic Cells, DERMATOLOGY, Gene Knock-In Techniques, Genetics, imiquimod, immune response, IMMUNE-RESPONSES, Immunization, Immunology, in situ, In vivo, Inbred BALB C, Inbred C57BL, INDUCTION, inflammation, Inflammation Mediators, Injections, Intradermal, knock-in, Langerhans Cells, LECTIN, Lectins, LYMPH, LYMPH NODE, Lymph Nodes, LYMPHATIC VESSEL, Lymphatic Vessels, mAb, Mannose-Binding Lectins, MEDIATOR, metabolism, Mice, Minor Histocompatibility Antigens, mouse, murine, Organ Culture Techniques, Ovum, pathology, physiology, Protein, Protein Transport, Rats, Receptor, Receptors, RESPONSES, Skin, SUBSETS, Surface, T-Lymphocytes, target, Team-Mueller, TLR7, transgenic},
pubstate = {published},
tppubtype = {article}
}
Noordegraaf Madelon, Flacher Vincent, Stoitzner Patrizia, Clausen Björn E
Functional redundancy of Langerhans cells and Langerin+ dermal dendritic cells in contact hypersensitivity Journal Article
In: The Journal of Investigative Dermatology, vol. 130, no. 12, pp. 2752–2759, 2010, ISSN: 1523-1747.
Abstract | Links | BibTeX | Tags: Animal, Animals, Antigen, Antigens, C-Type, CHS, contact, CONTACT HYPERSENSITIVITY, Dendritic Cells, DEPLETION, DERMAL DENDRITIC CELLS, Dermatitis, DERMIS, Diphtheria Toxin, Disease Models, Epidermis, function, Gene Knock-In Techniques, Genetics, Growth, HAPTEN, Haptens, Heparin-binding EGF-like Growth Factor, Hypersensitivity, Immunology, Inbred C57BL, INDUCTION, Intercellular Signaling Peptides and Proteins, LACKING, Langerhans Cells, LECTIN, Lectins, LYMPH, LYMPH NODE, Lymph Nodes, Mannose-Binding Lectins, metabolism, Mice, mouse, Mutant Strains, Organ Culture Techniques, pathology, Peptides, Poisons, Protein, Proteins, RESPONSES, signaling, Skin, Surface, Team-Mueller, Toxicity
@article{noordegraaf_functional_2010,
title = {Functional redundancy of Langerhans cells and Langerin+ dermal dendritic cells in contact hypersensitivity},
author = {Madelon Noordegraaf and Vincent Flacher and Patrizia Stoitzner and Björn E Clausen},
doi = {10.1038/jid.2010.223},
issn = {1523-1747},
year = {2010},
date = {2010-12-01},
journal = {The Journal of Investigative Dermatology},
volume = {130},
number = {12},
pages = {2752--2759},
abstract = {The relative roles of Langerhans cells (LC), dermal dendritic cells (DC), and, in particular, the recently discovered Langerin(+) dermal DC subset in the induction and control of contact hypersensitivity (CHS) responses remain controversial. Using an inducible mouse model, in which LC and other Langerin(+) DC can be depleted by injection of diphtheria toxin, we previously reported impaired transport of topically applied antigen to draining lymph nodes and reduced CHS in the absence of all Langerin(+) skin DC. In this study, we demonstrate that mice with a selective depletion of LC exhibit attenuated CHS only upon sensitization with a low hapten dose but not with a high hapten dose. In contrast, when painting a higher concentration of hapten onto the skin, which leads to increased antigen dissemination into the dermis, CHS is still diminished in mice lacking all Langerin(+) skin DC. Taken together, these data suggest that the magnitude of a CHS reaction depends on the number of skin DC, which have access to the hapten, rather than on the presence or absence of a particular skin DC population. LC and (Langerin(+)) dermal DC thus seem to have a redundant function in regulating CHS.},
keywords = {Animal, Animals, Antigen, Antigens, C-Type, CHS, contact, CONTACT HYPERSENSITIVITY, Dendritic Cells, DEPLETION, DERMAL DENDRITIC CELLS, Dermatitis, DERMIS, Diphtheria Toxin, Disease Models, Epidermis, function, Gene Knock-In Techniques, Genetics, Growth, HAPTEN, Haptens, Heparin-binding EGF-like Growth Factor, Hypersensitivity, Immunology, Inbred C57BL, INDUCTION, Intercellular Signaling Peptides and Proteins, LACKING, Langerhans Cells, LECTIN, Lectins, LYMPH, LYMPH NODE, Lymph Nodes, Mannose-Binding Lectins, metabolism, Mice, mouse, Mutant Strains, Organ Culture Techniques, pathology, Peptides, Poisons, Protein, Proteins, RESPONSES, signaling, Skin, Surface, Team-Mueller, Toxicity},
pubstate = {published},
tppubtype = {article}
}
Flacher Vincent, Sparber Florian, Tripp Christoph H, Romani Nikolaus, Stoitzner Patrizia
Targeting of epidermal Langerhans cells with antigenic proteins: attempts to harness their properties for immunotherapy Journal Article
In: Cancer immunology, immunotherapy: CII, vol. 58, no. 7, pp. 1137–1147, 2009, ISSN: 1432-0851.
Abstract | Links | BibTeX | Tags: Active, Animals, Antibodies, antibody, Antigen, Antigens, BLOOD, C-Type, cancer, CD, CD4-Positive T-Lymphocytes, CD4+ T cells, CD8-Positive T-Lymphocytes, CD8+ T cells, Dendritic Cells, DERMATOLOGY, DERMIS, Epidermis, Growth, Human, Humans, immune response, IMMUNE-RESPONSES, Immunization, Immunology, Immunotherapy, in situ, In vivo, Inbred BALB C, Inbred C57BL, INDUCTION, Langerhans Cells, LECTIN, Lectins, LYMPH, LYMPH NODE, Lymph Nodes, Major Histocompatibility Complex, Mannose-Binding Lectins, metabolism, methods, MHC class I, MHC class I molecules, Mice, Neoplasm, Neoplasms, OVALBUMIN, Patients, PROGENITORS, Protein, Proteins, RESPONSES, review, Skin, T CELLS, T-CELLS, Team-Mueller, therapy, tumor
@article{flacher_targeting_2009,
title = {Targeting of epidermal Langerhans cells with antigenic proteins: attempts to harness their properties for immunotherapy},
author = {Vincent Flacher and Florian Sparber and Christoph H Tripp and Nikolaus Romani and Patrizia Stoitzner},
doi = {10.1007/s00262-008-0563-9},
issn = {1432-0851},
year = {2009},
date = {2009-07-01},
journal = {Cancer immunology, immunotherapy: CII},
volume = {58},
number = {7},
pages = {1137--1147},
abstract = {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 fluorescently 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.},
keywords = {Active, Animals, Antibodies, antibody, Antigen, Antigens, BLOOD, C-Type, cancer, CD, CD4-Positive T-Lymphocytes, CD4+ T cells, CD8-Positive T-Lymphocytes, CD8+ T cells, Dendritic Cells, DERMATOLOGY, DERMIS, Epidermis, Growth, Human, Humans, immune response, IMMUNE-RESPONSES, Immunization, Immunology, Immunotherapy, in situ, In vivo, Inbred BALB C, Inbred C57BL, INDUCTION, Langerhans Cells, LECTIN, Lectins, LYMPH, LYMPH NODE, Lymph Nodes, Major Histocompatibility Complex, Mannose-Binding Lectins, metabolism, methods, MHC class I, MHC class I molecules, Mice, Neoplasm, Neoplasms, OVALBUMIN, Patients, PROGENITORS, Protein, Proteins, RESPONSES, review, Skin, T CELLS, T-CELLS, Team-Mueller, therapy, tumor},
pubstate = {published},
tppubtype = {article}
}