title: TLR-dependent phagosome tubulation in dendritic cells promotes phagosome cross-talk to optimize MHC-II antigen presentation.
abstract: Dendritic cells (DCs) phagocytose large particles like bacteria at sites of infection and progressively degrade them within maturing phagosomes. Phagosomes in DCs are also signaling platforms for pattern recognition receptors, such as Toll-like receptors (TLRs), and sites for assembly of cargo-derived peptides with major histocompatibility complex class II (MHC-II) molecules. Although TLR signaling from phagosomes stimulates presentation of phagocytosed antigens, the mechanisms underlying this enhancement and the cell surface delivery of MHC-II-peptide complexes from phagosomes are not known. We show that in DCs, maturing phagosomes extend numerous long tubules several hours after phagocytosis. Tubule formation requires an intact microtubule and actin cytoskeleton and MyD88-dependent phagosomal TLR signaling, but not phagolysosome formation or extensive proteolysis. In contrast to the tubules that emerge from endolysosomes after uptake of soluble ligands and TLR stimulation, the late-onset phagosomal tubules are not essential for delivery of phagosome-derived MHC-II-peptide complexes to the plasma membrane. Rather, tubulation promotes MHC-II presentation by enabling maximal cargo transfer among phagosomes that bear a TLR signature. Our data show that phagosomal tubules in DCs are functionally distinct from those that emerge from lysosomes and are unique adaptations of the phagocytic machinery that facilitate cargo exchange and antigen presentation among TLR-signaling phagosomes.
authors.affiliation: Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia, Philadelphia, PA 19104; Department of Physiology and.
authors.forename: Adriana R
authors.initials: AR
authors.lastname: Mantegazza
authors.affiliation: Department of Physiology and Cell and Molecular Biology Graduate Group, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104; and.
authors.forename: Allison L
authors.initials: AL
authors.lastname: Zajac
authors.affiliation: Department of Physiology and.
authors.forename: Alison
authors.initials: A
authors.lastname: Twelvetrees
authors.affiliation: Department of Physiology and.
authors.forename: Erika L F
authors.initials: EL
authors.lastname: Holzbaur
authors.affiliation: Section de Recherche, Institut Curie and INSERM U932, 75005 Paris, France.
authors.forename: Sebastián
authors.initials: S
authors.lastname: Amigorena
authors.affiliation: Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia, Philadelphia, PA 19104; Department of Physiology and marksm@mail.med.upenn.edu.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Marks
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D017951:Antigen Presentation / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology*; D000949:Histocompatibility Antigens Class II / Q000276:immunology*; D008070:Lipopolysaccharides; D008247:Lysosomes / Q000378:metabolism; D008810:Mice, Inbred C57BL; D008870:Microtubules / Q000378:metabolism; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism; D010455:Peptides / Q000378:metabolism; D010588:Phagosomes / Q000276:immunology*; D015398:Signal Transduction; D051197:Toll-Like Receptor 4 / Q000378:metabolism; D051193:Toll-Like Receptors / Q000378:metabolism*
chemical_list: D000199:Actins; D000949:Histocompatibility Antigens Class II; D008070:Lipopolysaccharides; D053594:Myeloid Differentiation Factor 88; D010455:Peptides; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors
keywords: Toll-like receptors; inflammation; major histocompatibility complex; microtubules; phagocytosis