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.
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We thank G. Cheng for technical support; L. Cavanagh, T. Junt and I.B. Mazo for discussions; and S. Massberg for contributing thoracic duct lymph data. Supported by the National Institutes of Health (AI061663, AR42689 and HL56949 to U.H.v.A.; and HL072056 and AI059610 to A.H.L.), the Giovanni Armenise-Harvard Foundation (R.B.) and the Schweizerische Stiftung für medizinisch-biologische Stipendien (P.S.).
The authors declare no competing financial interests.
Fully differentiated DCs in blood and thoracic duct lymph. (PDF 174 kb)
Clonal deletion of OT-II cells by adoptive transfer of different doses of DCs. (PDF 102 kb)
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Bonasio, R., Scimone, M., Schaerli, P. et al. Clonal deletion of thymocytes by circulating dendritic cells homing to the thymus. Nat Immunol 7, 1092–1100 (2006). https://doi.org/10.1038/ni1385
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