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Intrahepatic myeloid-cell aggregates enable local proliferation of CD8+ T cells and successful immunotherapy against chronic viral liver infection

Nature Immunology volume 14, pages 574–583 (2013)Cite this article

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Abstract

Chronic infection is difficult to overcome because of exhaustion or depletion of cytotoxic effector CD8+ T cells (cytotoxic T lymphoytes (CTLs)). Here we report that signaling via Toll-like receptors (TLRs) induced intrahepatic aggregates of myeloid cells that enabled the population expansion of CTLs (iMATEs: 'intrahepatic myeloid-cell aggregates for T cell population expansion') without causing immunopathology. In the liver, CTL proliferation was restricted to iMATEs that were composed of inflammatory monocyte–derived CD11b+ cells. Signaling via tumor-necrosis factor (TNF) caused iMATE formation that facilitated costimulation dependent on the receptor OX40 for expansion of the CTL population. The iMATEs arose during acute viral infection but were absent during chronic viral infection, yet they were still induced by TLR signaling. Such hepatic expansion of the CTL population controlled chronic viral infection of the liver after vaccination with DNA. Thus, iMATEs are dynamic structures that overcome regulatory cues that limit the population expansion of CTLs during chronic infection and can be used in new therapeutic vaccination strategies.

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Figure 1: Injection of TLR9 ligand results in more IL-12-treated CTLs in the liver.
Figure 2: Characterization of iMATEs in the liver after injection of TLR9 ligand.
Figure 3: CTL proliferation in iMATEs.
Figure 4: Phenotype of myeloid cells in iMATEs.
Figure 5: Hepatic myeloid cells support the expansion of the CTL population by providing costimulatory signals.
Figure 6: Improved clearance of viral infection from the liver by injection of TLR9 ligand.
Figure 7: Elimination of chronic AdHBV infection.

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Acknowledgements

We thank D. Kull, R. Hillermann, O. Seelbach, N. Simonavicius, M. Wolf and the flow cytometry core facility of the Institutes of Molecular Medicine and Experimental Immunology, University of Bonn for technical support. Supported by the Helmholtz Association (M.H.), the Hofschneider Foundation (M.H.), the European Research Council (LiverCancerMech; M.H.), the Helmholtz Alliance Preclinical Comprehensive Cancer Center (M.H.), Sonderforschungsbereich (36 to M.H., and 704, TR57 and 670 to P.K.), the Helmholtz Alliance on Immunotherapy of Cancer (P.K.), the Bundesministerium für Bildung und Forschung projects Virtual Liver and PeTra (P.K.) and the Excellence Cluster ImmunoSensation (P.K.).

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Authors and Affiliations

  1. Institutes of Molecular Medicine and Experimental Immunology, University of Bonn, Bonn, Germany

    Li-Rung Huang, Dirk Wohlleber, Ru-Lin Cheng, Zeinab Abdullah, Frank A Schildberg, Natalio Garbi, Christian Kurts & Percy A Knolle

  2. Institute of Virology Technische Universität München/Helmholtz Zentrum München, München, Germany

    Florian Reisinger, Ulrike Protzer & Mathias Heikenwalder

  3. Calvin, Phoebe, and Joan Snyder Institute for Infection, Immunity and Inflammation, University of Calgary, Calgary, Canada

    Craig N Jenne & Paul Kubes

  4. Institute of Pathology, University of Köln, Köln, Germany

    Margarete Odenthal & Hans-Peter Dienes

  5. Molecular Cell Biology and Immunology, VU Medical Center, Amsterdam, The Netherlands

    Nico van Rooijen

  6. Institute of Immunology, University of Mainz, Mainz, Germany

    Edgar Schmitt

  7. Division of Immune Regulation, La Jolla Institute for Allergy and Immunology, La Jolla, California, USA

    Michael Croft

  8. Institute of Virology, Technische Universität München, München, Germany

    Percy A Knolle

  9. Institute of Molecular Immunology, Technische Universität München, München, Germany

    Percy A Knolle

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Contributions

L.-R.H., D.W., F.R., R.-L.C., Z.A. and F.A.S. did the experiments; C.N.J. and P.K. designed and did intravital microscopy experiments; M.O. and H.-P.D. did electron microscopy studies; N.v.R., E.S., N.G. and M.C. contributed reagents and contributed to experimental design; C.K., U.P., M.H. and P.A.K. designed experiments; and L.-R.H., M.H. and P.A.K. wrote the manuscript.

Corresponding authors

Correspondence to Mathias Heikenwalder or Percy A Knolle.

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Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–7 (PDF 3452 kb)

Supplementary Video 1

Hepatic microvasculature and uptake of TLR9-L by sinusoidal cells. (MOV 3412 kb)

Supplementary Video 2

Hepatic microvasculature and uptake of TLR9-L by sinusoidal cells. (MOV 4486 kb)

Supplementary Video 3

Circulating CD11b+ cells adhere in sinusoids after TLR9-L application. (MOV 6787 kb)

Supplementary Video 4

Circulating CD11b+ cells adhere in sinusoids after TLR9-L application. (MOV 4230 kb)

Supplementary Video 5

CD11b+ cells form non-perfused structures, iMATEs. (MOV 6593 kb)

Supplementary Video 6

CD11b+ cells form non-perfused structures, iMATEs. (MOV 5457 kb)

Supplementary Video 7

CD11b+ cells form non-perfused structures, iMATEs. (MOV 1295 kb)

Supplementary Video 8

CD11b+ cells form non-perfused structures, iMATEs. (MOV 4833 kb)

Supplementary Video 9

CD8+ T cells migrate slowly within iMATEs. (MOV 11059 kb)

Supplementary Video 10

3D structures of iMATEs. (MOV 3268 kb)

Supplementary Video 11

3D structures of iMATEs. (MOV 3577 kb)

Supplementary Video 12

3D structures of iMATEs. (MOV 5917 kb)

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Huang, LR., Wohlleber, D., Reisinger, F. et al. Intrahepatic myeloid-cell aggregates enable local proliferation of CD8+ T cells and successful immunotherapy against chronic viral liver infection. Nat Immunol 14, 574–583 (2013). https://doi.org/10.1038/ni.2573

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