title: Effective collaboration between marginal metallophilic macrophages and CD8+ dendritic cells in the generation of cytotoxic T cells.
abstract: The spleen is the lymphoid organ that induces immune responses toward blood-borne pathogens. Specialized macrophages in the splenic marginal zone are strategically positioned to phagocytose pathogens and cell debris, but are not known to play a role in the activation of T-cell responses. Here we demonstrate that splenic marginal metallophilic macrophages (MMM) are essential for cross-presentation of blood-borne antigens by splenic dendritic cells (DCs). Our data demonstrate that antigens targeted to MMM as well as blood-borne adenoviruses are efficiently captured by MMM and exclusively transferred to splenic CD8(+) DCs for cross-presentation and for the activation of cytotoxic T lymphocytes. Depletion of macrophages in the marginal zone prevents cytotoxic T-lymphocyte activation by CD8(+) DCs after antibody targeting or adenovirus infection. Moreover, we show that tumor antigen targeting to MMM is very effective as antitumor immunotherapy. Our studies point to an important role for splenic MMM in the initial steps of CD8(+) T-cell immunity by capturing and concentrating blood-borne antigens and the transfer to cross-presenting DCs which can be used to design vaccination strategies to induce antitumor cytotoxic T-cell immunity.
authors.affiliation: Department of Molecular Cell Biology and Immunology, VU University Medical Center, 1007 MB Amsterdam, The Netherlands.
authors.forename: Ronald
authors.initials: R
authors.lastname: Backer
authors.forename: Timo
authors.initials: T
authors.lastname: Schwandt
authors.forename: Mascha
authors.initials: M
authors.lastname: Greuter
authors.forename: Marije
authors.initials: M
authors.lastname: Oosting
authors.forename: Frank
authors.initials: F
authors.lastname: Jüngerkes
authors.forename: Thomas
authors.initials: T
authors.lastname: Tüting
authors.forename: Louis
authors.initials: L
authors.lastname: Boon
authors.forename: Tom
authors.initials: T
authors.lastname: O'Toole
authors.forename: Georg
authors.initials: G
authors.lastname: Kraal
authors.forename: Andreas
authors.initials: A
authors.lastname: Limmer
authors.forename: Joke M M
authors.initials: JM
authors.lastname: den Haan
mesh_terms: D000818:Animals; D017951:Antigen Presentation / Q000276:immunology; D050071:Bone Density Conservation Agents / Q000494:pharmacology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D004002:Clodronic Acid / Q000494:pharmacology; D003713:Dendritic Cells / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology; D008264:Macrophages / Q000187:drug effects / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D010047:Ovalbumin / Q000276:immunology; D013154:Spleen / Q000166:cytology / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*
chemical_list: D050071:Bone Density Conservation Agents; D004002:Clodronic Acid; D010047:Ovalbumin