title: TLR signals induce phagosomal MHC-I delivery from the endosomal recycling compartment to allow cross-presentation.
abstract: Adaptation of the endoplasmic reticulum (ER) pathway for MHC class I (MHC-I) presentation in dendritic cells enables cross-presentation of peptides derived from phagocytosed microbes, infected cells, or tumor cells to CD8 T cells. How these peptides intersect with MHC-I molecules remains poorly understood. Here, we show that MHC-I selectively accumulate within phagosomes carrying microbial components, which engage Toll-like receptor (TLR) signaling. Although cross-presentation requires Sec22b-mediated phagosomal recruitment of the peptide loading complex from the ER-Golgi intermediate compartment (ERGIC), this step is independent of TLR signaling and does not deliver MHC-I. Instead, MHC-I are recruited from an endosomal recycling compartment (ERC), which is marked by Rab11a, VAMP3/cellubrevin, and VAMP8/endobrevin and holds large reserves of MHC-I. While Rab11a activity stocks ERC stores with MHC-I, MyD88-dependent TLR signals drive IκB-kinase (IKK)2-mediated phosphorylation of phagosome-associated SNAP23. Phospho-SNAP23 stabilizes SNARE complexes orchestrating ERC-phagosome fusion, enrichment of phagosomes with ERC-derived MHC-I, and subsequent cross-presentation during infection.
authors.affiliation: Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Graduate School of Biological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Priyanka
authors.initials: P
authors.lastname: Nair-Gupta
authors.affiliation: Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Alessia
authors.initials: A
authors.lastname: Baccarini
authors.affiliation: Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Graduate School of Biological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Navpreet
authors.initials: N
authors.lastname: Tung
authors.affiliation: Institute of Biochemistry, Biocenter, Cluster of Excellence-Macromolecular Complexes, Goethe-University Frankfurt, Max-von-Laue Strasse 9, 60438 Frankfurt am Main, Germany.
authors.forename: Fabian
authors.initials: F
authors.lastname: Seyffer
authors.affiliation: Cell Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Oliver
authors.initials: O
authors.lastname: Florey
authors.affiliation: Department of Molecular and Cellular Biochemistry, University of Kentucky College of Medicine, Lexington, KY 40536, USA.
authors.forename: Yunjie
authors.initials: Y
authors.lastname: Huang
authors.affiliation: Department of Molecular and Cellular Biochemistry, University of Kentucky College of Medicine, Lexington, KY 40536, USA.
authors.forename: Meenakshi
authors.initials: M
authors.lastname: Banerjee
authors.affiliation: Cell Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Overholtzer
authors.affiliation: Experimental Cell Biology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Roche
authors.affiliation: Institute of Biochemistry, Biocenter, Cluster of Excellence-Macromolecular Complexes, Goethe-University Frankfurt, Max-von-Laue Strasse 9, 60438 Frankfurt am Main, Germany.
authors.forename: Robert
authors.initials: R
authors.lastname: Tampé
authors.affiliation: Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Brian D
authors.initials: BD
authors.lastname: Brown
authors.affiliation: Department of Hematopoiesis, Sanquin Research and Landsteiner Laboratory, Plesmanlaan 125, 1066CX Amsterdam, the Netherlands.
authors.forename: Derk
authors.initials: D
authors.lastname: Amsen
authors.affiliation: Department of Molecular and Cellular Biochemistry, University of Kentucky College of Medicine, Lexington, KY 40536, USA.
authors.forename: Sidney W
authors.initials: SW
authors.lastname: Whiteheart
authors.affiliation: Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Electronic address: julie.blander@mssm.edu.
authors.forename: J Magarian
authors.initials: JM
authors.lastname: Blander
mesh_terms: D000818:Animals; D017951:Antigen Presentation; D003713:Dendritic Cells / Q000276:immunology; D011992:Endosomes / Q000378:metabolism*; D015395:Histocompatibility Antigens Class I / Q000378:metabolism; D008221:Lymphoid Tissue; D051379:Mice; D010047:Ovalbumin / Q000276:immunology; D010587:Phagocytosis; D010588:Phagosomes / Q000378:metabolism*; D010766:Phosphorylation; D021381:Protein Transport; D050766:Qb-SNARE Proteins / Q000378:metabolism; D050767:Qc-SNARE Proteins / Q000378:metabolism; D051193:Toll-Like Receptors / Q000276:immunology / Q000378:metabolism*; D020691:rab GTP-Binding Proteins / Q000378:metabolism; D000099193:rab11 GTP-Binding Proteins
chemical_list: D015395:Histocompatibility Antigens Class I; D010047:Ovalbumin; D050766:Qb-SNARE Proteins; D050767:Qc-SNARE Proteins; D051193:Toll-Like Receptors; D020691:rab GTP-Binding Proteins; D000099193:rab11 GTP-Binding Proteins; C107017:Snap23 protein, mouse
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