Clonal deletion of thymocytes by circulating dendritic cells homing to the thymus.
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.
Bonasio
Roberto
R
The CBR Institute for Biomedical Research, Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, 02115, USA.
Scimone
M Lucila
ML
Schaerli
Patrick
P
Grabie
Nir
N
Lichtman
Andrew H
AH
von Andrian
Ulrich H
UH
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
D015704:CD4 Antigens; D039041:Integrin alpha4beta1; D053645:Interleukin-2 Receptor alpha Subunit; D019007:P-Selectin; D019010:Vascular Cell Adhesion Molecule-1; D010047:Ovalbumin