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.
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Change history
29 September 2006
In the version of this article initially published, the third sentence in the legend of Figure 6 is incorrect. The correct sentence should read “*, P < 0.01, and **, P < 0.001, compared with DCs”. In the last sentence of the legend to Figure 8, ‘obtainted’ should read ‘obtained’. On page 1098, in the first sentence of the first full paragraph, ‘fused’ should read ‘used’. These errors have been corrected in the HTML and PDF versions of the article.
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Acknowledgements
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.).
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R.B. designed and executed all experiments, unless otherwise stated; M.L.S. equally contributed to the design and realization of all adoptive transfers (Figs. 2,3,4,5,6); P.S. generated parabiotic mice; N.G. and A.H.L. provided CMy-mOVA-transgenic mice; and R.B. and U.H.v.A. prepared the manuscript with help from M.L.S.
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Supplementary Fig. 1
Fully differentiated DCs in blood and thoracic duct lymph. (PDF 174 kb)
Supplementary Fig. 3
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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DOI: https://doi.org/10.1038/ni1385
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