Dendritic cells are efficient antigen presenting cells for the induction of immunity and in some cases, tolerance. However, mechanisms for antigen (Ag) uptake, processing, and presentation are not understood. Recent evidence reveals that DCs are rich in specialized intracellular vacuoles in which antigenic peptides gain excess to MHC molecules. Also, it has recently been shown that MIIVs or CIIVs of DCs express DEC-205, a receptor for adsorptive uptake and presentation. Molecular cloning showed DEC-205 to be a group VI C-type lectin with 10 carbohydrate recognition domains. DEC-205 may well be a receptor that DCs and thymic epithelium use to capture Ags and target endocytic vesicles for presentation.
The aims are directed to elucidating the uptake and presentation mechanisms of DCs, with emphasis on the precise role of DEC-205 in endocytosis and targeting. This application proposes: 1) That DCs have an endocytic system specialized to internalize antigens and present these on MHC Class II. 2) That DEC-205 itself targets to intracellular vacuoles that lie beyond rapidly recycling early endosomes, particularly CIIVs. 3) That DCs can prevent particulate antigens on MHC class II and perhaps class I, as long as these are appropriately internalized and transported via antibodies to DEC-205. 4) That two separate regions in the cytoplasmic tail of DEC-205 mediate adsorptive uptake and presentation respectively. 5) That the cytoplasmic tail of DEC-205 will deliver ligands to antigen presenting late endosomes and thereby differ in function from the tails of other adsorptive endocytic receptors (the macrophage mannose receptor and low density lipoprotein receptor). 6) That the cell biological role of DEC-205 in epithelia and brain endothelium will be analogous to DCs, i.e., to target ligands away from terminal digestion in lysosomes and towards late endosomes utilized in transcytosis and/or peptide recycling.
|Loschko, Jakob; Rieke, Gereon J; Schreiber, Heidi A et al. (2016) Inducible targeting of cDCs and their subsets in vivo. J Immunol Methods 434:32-8|
|Loschko, Jakob; Schreiber, Heidi A; Rieke, Gereon J et al. (2016) Absence of MHC class II on cDCs results in microbial-dependent intestinal inflammation. J Exp Med 213:517-34|
|Lee, Jaeyop; Breton, Gaëlle; Oliveira, Thiago Yukio Kikuchi et al. (2015) Restricted dendritic cell and monocyte progenitors in human cord blood and bone marrow. J Exp Med 212:385-99|
|Lee, Jaeyop; Breton, Gaëlle; Aljoufi, Arafat et al. (2015) Clonal analysis of human dendritic cell progenitor using a stromal cell culture. J Immunol Methods 425:21-26|
|Silva-Sánchez, Aarón; Meza-Pérez, Selene; Flores-Langarica, Adriana et al. (2015) ESAT-6 Targeting to DEC205+ Antigen Presenting Cells Induces Specific-T Cell Responses against ESAT-6 and Reduces Pulmonary Infection with Virulent Mycobacterium tuberculosis. PLoS One 10:e0124828|
|Breton, Gaëlle; Lee, Jaeyop; Zhou, Yu Jerry et al. (2015) Circulating precursors of human CD1c+ and CD141+ dendritic cells. J Exp Med 212:401-13|
|Breton, Gaëlle; Lee, Jaeyop; Liu, Kang et al. (2015) Defining human dendritic cell progenitors by multiparametric flow cytometry. Nat Protoc 10:1407-22|
|Pantel, Austin; Teixeira, Angela; Haddad, Elias et al. (2014) Direct type I IFN but not MDA5/TLR3 activation of dendritic cells is required for maturation and metabolic shift to glycolysis after poly IC stimulation. PLoS Biol 12:e1001759|
|Mollah, Shamim A; Dobrin, Joseph S; Feder, Rachel E et al. (2014) Flt3L dependence helps define an uncharacterized subset of murine cutaneous dendritic cells. J Invest Dermatol 134:1265-1275|
|Anandasabapathy, Niroshana; Feder, Rachel; Mollah, Shamim et al. (2014) Classical Flt3L-dependent dendritic cells control immunity to protein vaccine. J Exp Med 211:1875-91|
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