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Clonal deletion of thymocytes by circulating dendritic cells homing to the thymus

Nature Immunology volume 7, pages 1092–1100 (2006)Cite this article

A Corrigendum to this article was published on 01 November 2006

This article has been updated

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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Figure 1: Blood-borne DCs are recruited to the thymus and localize to the medulla.
Figure 2: Phenotype of DCs recruited to the thymus.
Figure 3: P-selectin and VLA-4–VCAM-1 interactions mediate the recruitment of DCs to the thymus.
Figure 4: Gαi-mediated signaling is required for homing of DCs to the thymus.
Figure 5: Circulating DCs recruited to the thymus induce apoptosis and clonal deletion of antigen-specific thymocytes.
Figure 6: Presentation of agonist peptide by blood-borne DCs does not induce intrathymic differentiation of OT-II regulatory T cells.
Figure 7: Migration of endogenous DCs to the thymus.
Figure 8: Clonal deletion of OT-II thymocytes in CMy-mOVA mice depends on α4 integrin function.

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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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Authors and Affiliations

  1. Department of Pathology, The CBR Institute for Biomedical Research, Brigham and Women's Hospital, Harvard Medical School, Boston, 02115, Massachusetts, USA

    Roberto Bonasio, M Lucila Scimone, Patrick Schaerli & Ulrich H von Andrian

  2. Immunology Research Division and Vascular Research Division, Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, 02115, Massachusetts, USA

    Nir Grabie & Andrew H Lichtman

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Contributions

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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Correspondence to Ulrich H von Andrian.

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Supplementary information

Supplementary Fig. 1

Fully differentiated DCs in blood and thoracic duct lymph. (PDF 174 kb)

Supplementary Fig. 2

Schematic diagram of the experimental protocol for the generation of mixed BM chimeras in figures 5, 6 and supplementary figure 3. (PDF 46 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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