title: TIM-4, expressed by medullary macrophages, regulates respiratory tolerance by mediating phagocytosis of antigen-specific T cells.
abstract: Respiratory exposure to antigen induces T cell tolerance via several overlapping mechanisms that limit the immune response. While the mechanisms involved in the development of Treg cells have received much attention, those that result in T cell deletion are largely unknown. Herein, we show that F4/80(+) lymph node medullary macrophages expressing TIM-4, a phosphatidylserine receptor, remove antigen-specific T cells during respiratory tolerance, thereby reducing secondary T cell responses. Blockade of TIM-4 inhibited the phagocytosis of antigen-specific T cells by TIM-4 expressing lymph node medullary macrophages, resulting in an increase in the number of antigen-specific T cells and the abrogation of respiratory tolerance. Moreover, specific depletion of medullary macrophages inhibited the induction of respiratory tolerance, highlighting the key role of TIM-4 and medullary macrophages in tolerance. Therefore, TIM-4-mediated clearance of antigen specific T cells represents an important previously unrecognized mechanism regulating respiratory tolerance.
authors.affiliation: Division of Immunology, Children's Hospital Boston, and Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: L A
authors.initials: LA
authors.lastname: Albacker
authors.forename: S
authors.initials: S
authors.lastname: Yu
authors.forename: D
authors.initials: D
authors.lastname: Bedoret
authors.forename: W-L
authors.initials: WL
authors.lastname: Lee
authors.forename: S E
authors.initials: SE
authors.lastname: Umetsu
authors.forename: S
authors.initials: S
authors.lastname: Monahan
authors.forename: G J
authors.initials: GJ
authors.lastname: Freeman
authors.forename: D T
authors.initials: DT
authors.lastname: Umetsu
authors.forename: R H
authors.initials: RH
authors.lastname: DeKruyff
mesh_terms: D000281:Administration, Intranasal; D019264:Adoptive Transfer; D000818:Animals; D019138:Antibodies, Blocking / Q000008:administration & dosage; D000941:Antigens / Q000276:immunology; D000943:Antigens, Differentiation / Q000378:metabolism; D002478:Cells, Cultured; D007108:Immune Tolerance; D008198:Lymph Nodes / Q000473:pathology; D008264:Macrophages / Q000276:immunology*; D008565:Membrane Proteins / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D010047:Ovalbumin / Q000276:immunology; D010587:Phagocytosis / Q000276:immunology; D012130:Respiratory Hypersensitivity / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: D019138:Antibodies, Blocking; D000941:Antigens; D000943:Antigens, Differentiation; D008565:Membrane Proteins; C500399:TIM-4 protein, mouse; C036763:monocyte-macrophage differentiation antigen; D010047:Ovalbumin