ABSTRACT
Langerin is a C-type lectin expressed by a subset of dendritic leukocytes, the Langerhans cells (LC). Langerin is a cell surface receptor that induces the formation of an LC-specific organelle, the Birbeck granule (BG). We generated a langerin(-/-) mouse on a C57BL/6 background which did not display any macroscopic aberrant development. In the absence of langerin, LC were detected in normal numbers in the epidermis but the cells lacked BG. LC of langerin(-/-) mice did not present other phenotypic alterations compared to wild-type littermates. Functionally, the langerin(-/-) LC were able to capture antigen, to migrate towards skin draining lymph nodes, and to undergo phenotypic maturation. In addition, langerin(-/-) mice were not impaired in their capacity to process native OVA protein for I-A(b)-restricted presentation to CD4(+) T lymphocytes or for H-2K(b)-restricted cross-presentation to CD8(+) T lymphocytes. langerin(-/-) mice inoculated with mannosylated or skin-tropic microorganisms did not display an altered pathogen susceptibility. Finally, chemical mutagenesis resulted in a similar rate of skin tumor development in langerin(-/-) and wild-type mice. Overall, our data indicate that langerin and BG are dispensable for a number of LC functions. The langerin(-/-) C57BL/6 mouse should be a valuable model for further functional exploration of langerin and the role of BG.
Subject(s)
Antigens, Surface/genetics , Antigens, Surface/physiology , Islets of Langerhans/cytology , Langerhans Cells/cytology , Lectins, C-Type/genetics , Lectins, C-Type/physiology , Mannose-Binding Lectins/genetics , Mannose-Binding Lectins/physiology , 9,10-Dimethyl-1,2-benzanthracene , Animals , Antigens/metabolism , Blastocyst/metabolism , CD4-Positive T-Lymphocytes/metabolism , CD8-Positive T-Lymphocytes/metabolism , Carcinogens , Cell Movement , Cell Physiological Phenomena , Cytoplasmic Granules/metabolism , Dendritic Cells , Dose-Response Relationship, Drug , Electroporation , Embryo, Mammalian/cytology , Flow Cytometry , Genetic Vectors , Immunohistochemistry , Islets of Langerhans/physiology , Kinetics , Lectins/metabolism , Lymph Nodes/metabolism , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Mice, Transgenic , Microscopy, Electron , Models, Genetic , Mutagenesis , Mutation , Neoplasms/chemically induced , Ovalbumin/metabolism , Phenotype , Stem Cells/cytologyABSTRACT
Dendritic cells (DCs) are antigen-presenting cells with the unique capacity to initiate primary immune responses. Dendritic cells have a remarkable pattern of differentiation (maturation) that exhibits highly specific mechanisms to control antigen presentation restricted by major histocompatibility complex (MHC). MHC class I molecules present to CD8(+) cytotoxic T cells peptides that are derived mostly from cytosolic proteins, which are ubiquitinated and then degraded by the proteasome. Here we show that on inflammatory stimulation, DCs accumulate newly synthesized ubiquitinated proteins in large cytosolic structures. These structures are similar to, but distinct from, aggresomes and inclusion bodies observed in many amyloid diseases. Notably, these dendritic cell aggresome-like induced structures (DALIS) are transient, require continuous protein synthesis and do not affect the ubiquitin-proteasome pathway. Our observations suggest the existence of an organized prioritization of protein degradation in stimulated DCs, which is probably important for regulating MHC class I presentation during maturation.
