title: Host ER-parasitophorous vacuole interaction provides a route of entry for antigen cross-presentation in Toxoplasma gondii-infected dendritic cells.
abstract: Toxoplasma gondii tachyzoites infect host cells by an active invasion process leading to the formation of a specialized compartment, the parasitophorous vacuole (PV). PVs resist fusion with host cell endosomes and lysosomes and are thus distinct from phagosomes. Because the parasite remains sequestered within the PV, it is unclear how T. gondii-derived antigens (Ag's) access the major histocompatibility complex (MHC) class I pathway for presentation to CD8(+) T cells. We demonstrate that recruitment of host endoplasmic reticulum (hER) to the PV in T. gondii-infected dendritic cells (DCs) directly correlates with cross-priming of CD8(+) T cells. Furthermore, we document by immunoelectron microscopy the transfer of hER components into the PV, a process indicative of direct fusion between the two compartments. In strong contrast, no association between hER and phagosomes or Ag presentation activity was observed in DCs containing phagocytosed live or dead parasites. Importantly, cross-presentation of parasite-derived Ag in actively infected cells was blocked when hER retrotranslocation was inhibited, indicating that the hER serves as a conduit for the transport of Ag between the PV and host cytosol. Collectively, these findings demonstrate that pathogen-driven hER-PV interaction can serve as an important mechanism for Ag entry into the MHC class I pathway and CD8(+) T cell cross-priming.
authors.affiliation: Immunobiology Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA. rgoldszmid@niaid.nih.gov
authors.forename: Romina S
authors.initials: RS
authors.lastname: Goldszmid
authors.forename: Isabelle
authors.initials: I
authors.lastname: Coppens
authors.forename: Avital
authors.initials: A
authors.lastname: Lev
authors.forename: Pat
authors.initials: P
authors.lastname: Caspar
authors.forename: Ira
authors.initials: I
authors.lastname: Mellman
authors.forename: Alan
authors.initials: A
authors.lastname: Sher
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D000953:Antigens, Protozoan / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D045142:Cross-Priming / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology* / Q000469:parasitology* / Q000648:ultrastructure; D004721:Endoplasmic Reticulum / Q000276:immunology*; D005455:Fluorescent Antibody Technique; D007150:Immunohistochemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D046529:Microscopy, Electron, Transmission; D014122:Toxoplasma / Q000276:immunology*; D014123:Toxoplasmosis / Q000276:immunology*; D014617:Vacuoles / Q000276:immunology* / Q000469:parasitology
chemical_list: D000953:Antigens, Protozoan