title: Clonal deletion of thymocytes by circulating dendritic cells homing to the thymus.
abstract: Dendritic cell (DC) presentation of self antigen to thymocytes is essential to the establishment of central tolerance. We show here that circulating DCs were recruited to the thymic medulla through a three-step adhesion cascade involving P-selectin, interactions of the integrin VLA-4 with its ligand VCAM-1, and pertussis toxin-sensitive chemoattractant signaling. Ovalbumin-specific OT-II thymocytes were selectively deleted after intravenous injection of antigen-loaded exogenous DCs. We documented migration of endogenous DCs to the thymus in parabiotic mice and after painting mouse skin with fluorescein isothiocyanate. Antibody to VLA-4 blocked the accumulation of peripheral tissue-derived DCs in the thymus and also inhibited the deletion of OT-II thymocytes in mice expressing membrane-bound ovalbumin in cardiac myocytes. These findings identify a migratory route by which peripheral DCs may contribute to central tolerance.
authors.affiliation: The CBR Institute for Biomedical Research, Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, 02115, USA.
authors.forename: Roberto
authors.initials: R
authors.lastname: Bonasio
authors.forename: M Lucila
authors.initials: ML
authors.lastname: Scimone
authors.forename: Patrick
authors.initials: P
authors.lastname: Schaerli
authors.forename: Nir
authors.initials: N
authors.lastname: Grabie
authors.forename: Andrew H
authors.initials: AH
authors.lastname: Lichtman
authors.forename: Ulrich H
authors.initials: UH
authors.lastname: von Andrian
mesh_terms: D000818:Animals; D017951:Antigen Presentation; D015704:CD4 Antigens / Q000032:analysis; D002465:Cell Movement; D017637:Clonal Deletion / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology*; D039041:Integrin alpha4beta1 / Q000378:metabolism; D053645:Interleukin-2 Receptor alpha Subunit / Q000032:analysis; D051379:Mice; D008810:Mice, Inbred C57BL; D010047:Ovalbumin / Q000276:immunology; D019007:P-Selectin / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D013950:Thymus Gland / Q000166:cytology / Q000276:immunology*; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
chemical_list: D015704:CD4 Antigens; D039041:Integrin alpha4beta1; D053645:Interleukin-2 Receptor alpha Subunit; D019007:P-Selectin; D019010:Vascular Cell Adhesion Molecule-1; D010047:Ovalbumin