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A platelet-mediated system for shuttling blood-borne bacteria to CD8α+ dendritic cells depends on glycoprotein GPIb and complement C3

Nature Immunology volume 12, pages 1194–1201 (2011)Cite this article

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Abstract

The acquisition of pathogen-derived antigen by dendritic cells (DCs) is a key event in the generation of cytotoxic CD8+ T cell responses. In mice, the intracellular bacterium Listeria monocytogenes is directed from the blood to splenic CD8α+ DCs. We report that L. monocytogenes rapidly associated with platelets in the bloodstream in a manner dependent on GPIb and complement C3. Platelet association targeted a small but immunologically important portion of L. monocytogenes to splenic CD8α+ DCs, diverting bacteria from swift clearance by other, less immunogenic phagocytes. Thus, an effective balance is established between maintaining sterility of the circulation and induction of antibacterial immunity by DCs. Other Gram-positive bacteria also were rapidly tagged by platelets, revealing a broadly active shuttling mechanism for systemic bacteria.

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Figure 1: Complement C3 mediates efficient L. monocytogenes (LM) infection of the spleen.
Figure 2: Complement C3 enables efficient L. monocytogenes entry into splenic CD8α+ DCs.
Figure 3: Complement C3 and platelet GPIb enable bacteria-platelet interactions that mediate L. monocytogenes shuttling to splenic CD8α+ DCs.
Figure 4: Platelets are specifically taken up by splenic CD8α+ DCs and mediate L. monocytogenes delivery to this cell population.
Figure 5: Impaired anti-L. monocytogenes CD8+ T cell population expansion after inefficient platelet-mediated bacterial targeting to CD8α+ DCs.
Figure 6: Lack of complement-mediated platelet association leads to accelerated bacterial clearance.
Figure 7: C3-mediated platelet association among various Gram-positive bacteria.

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Acknowledgements

We thank S. Gordon, P. Lachmann and H. Wagner for input; M. Botto (Imperial College, London) for C1qa−/− mice; M. Carroll (Harvard Medical School) for C3−/− and C4b−/− mice; C. Gerard (Harvard Medical School) for C3ar−/− mice; F. Petry (Johannes Gutenberg University of Mainz, Germany) for C1qa−/− mice; M. van der Linden (University Hospital Aachen, Germany) for Streptococcus strains; S. Feihl and V. Greifenberg for bacterial typing; L. Henkel, M. Schiemann and K. Wild for flow cytometry cell sorting; K. Mink, S. Vieweg and A. Wanisch for experimental assistance; and L. Layland for support preparing the manuscript. Supported by the German Research Foundation SFB 914 (TP-B4 to A.V. and D.H.B.) and SFB 576 (TP-A8 to D.H.B.), the Swiss National Foundation (3100AO-100779/2 and 3100AO-100068/2 to H.H. and R.M.Z.), the German Center for Infection Research (DZIF; D.H.B.) and the European Commission (Marie Curie Fellowship to A.V.).

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Author notes

  1. Alexander A Navarini

    Present address: Present address: Department of Dermatology, University Hospital Zurich, Zurich, Switzerland.,

  2. Rolf M Zinkernagel, Hans Hengartner and Dirk H Busch: These authors share senior authorship.

Authors and Affiliations

  1. Institute for Medical Microbiology, Immunology and Hygiene, and Focus Group, Clinical Cell Processing and Purification, Institute for Advanced Study, Technische Universität München, Munich, Germany

    Admar Verschoor, Michael Neuenhahn, Patricia Graef, Ann Plaumann, Amelie Seidlmeier & Dirk H Busch

  2. Institute for Experimental Immunology, University Hospital Zurich, Zurich, Switzerland

    Admar Verschoor, Alexander A Navarini, Rolf M Zinkernagel & Hans Hengartner

  3. German Mouse Clinic, Helmholtz Zentrum München, Neuherberg, Germany

    Admar Verschoor & Dirk H Busch

  4. Clinical Cooperation Groups Antigen-Specific Immunotherapy Helmholtz Zentrum München and Immune Monitoring, Technische Universität München, Munich, Germany

    Michael Neuenhahn & Dirk H Busch

  5. Vascular Medicine, University Hospital Würzburg and Rudolf Virchow Center, DFG Research Center for Experimental Biomedicine, University of Würzburg, Würzburg, Germany

    Bernhard Nieswandt

  6. Deutsches Herzzentrum, Klinik für Herz und Kreislauferkrankungen, Technische Universität München, Munich, Germany

    Steffen Massberg

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Contributions

A.V., M.N., A.A.N., A.P., A.S. and P.G. did experiments; B.N. and S.M. supplied reagents and assisted with data interpretation; A.V. and D.H.B. conceived the study; A.V., M.N., A.A.N. and P.G. analyzed the data; A.V., H.H., R.M.Z. and D.H.B. planned the experiments and supervised the study. A.V. and D.H.B. wrote the paper.

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Correspondence to Admar Verschoor or Dirk H Busch.

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Verschoor, A., Neuenhahn, M., Navarini, A. et al. A platelet-mediated system for shuttling blood-borne bacteria to CD8α+ dendritic cells depends on glycoprotein GPIb and complement C3. Nat Immunol 12, 1194–1201 (2011). https://doi.org/10.1038/ni.2140

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