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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 574583 (2013) | Download Citation


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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  1. 1.

    Hepatic T cells and liver tolerance. Nat. Rev. Immunol. 3, 51–62 (2003).

  2. 2.

    & Antigen-presenting cell function in the tolerogenic liver environment. Nat. Rev. Immunol. 10, 753–766 (2010).

  3. 3.

    The liver as a lymphoid organ. Annu. Rev. Immunol. 27, 147–163 (2009).

  4. 4.

    , & Living in the liver: hepatic infections. Nat. Rev. Immunol. 12, 201–213 (2012).

  5. 5.

    , & Oscillating CD8+ T cell effector functions after antigen recognition in the liver. Immunity 23, 53–63 (2005).

  6. 6.

    et al. Functional skewing of the global CD8 T cell population in chronic hepatitis B virus infection. J. Exp. Med. 205, 2111–2124 (2008).

  7. 7.

    et al. Bim-mediated deletion of antigen-specific CD8 T cells in patients unable to control HBV infection. J. Clin. Invest. 118, 1835–1845 (2008).

  8. 8.

    et al. CD8+ T lymphocytes protective against malaria liver stages are primed in skin-draining lymph nodes. Nat. Med. 13, 1035–1041 (2007).

  9. 9.

    et al. Prolonged antigen presentation is required for optimal CD8+ T cell responses against malaria liver stage parasites. PLoS Pathog. 6, e1000877 (2010).

  10. 10.

    & Feedback regulation of pathogen-specific T cell priming. Immunity 18, 499–511 (2003).

  11. 11.

    et al. Migration of cytotoxic lymphocytes in cell cycle permits local MHC I-dependent control of division at sites of viral infection. J. Exp. Med. 208, 747–759 (2011).

  12. 12.

    , , , & Tertiary lymphoid organs in infection and autoimmunity. Trends Immunol. 33, 297–305 (2012).

  13. 13.

    et al. Role of inducible bronchus associated lymphoid tissue (iBALT) in respiratory immunity. Nat. Med. 10, 927–934 (2004).

  14. 14.

    et al. The development of inducible bronchus-associated lymphoid tissue depends on IL-17. Nat. Immunol. 12, 639–646 (2011).

  15. 15.

    et al. Macrophage and T cell dynamics during the development and disintegration of mycobacterial granulomas. Immunity 28, 271–284 (2008).

  16. 16.

    et al. Intravital imaging reveals limited antigen presentation and T cell effector function in mycobacterial granulomas. Immunity 34, 807–819 (2011).

  17. 17.

    , & CD8 T cell clonal expansion and development of effector function require prolonged exposure to antigen, costimulation, and signal 3 cytokine. J. Immunol. 171, 5165–5171 (2003).

  18. 18.

    , , , & Inhibition of TCR-induced CD8 T cell death by IL-12: regulation of Fas ligand and cellular FLIP expression and caspase activation by IL-12. J. Immunol. 170, 2456–2460 (2003).

  19. 19.

    et al. Ex vivo culture with interleukin (IL)-12 improves CD8+ T-cell adoptive immunotherapy for murine leukemia independent of IL-18 or IFN-γ but requires perforin. Cancer Res. 66, 4913–4921 (2006).

  20. 20.

    & Lymphotoxin/light, lymphoid microenvironments and autoimmune disease. Nat. Rev. Immunol. 3, 642–655 (2003).

  21. 21.

    , , & Lymphoid organ development: from ontogeny to neogenesis. Nat. Immunol. 7, 344–353 (2006).

  22. 22.

    , , , & TNF/iNOS-producing dendritic cells mediate innate immune defense against bacterial infection. Immunity 19, 59–70 (2003).

  23. 23.

    et al. Signals required for programming effector and memory development by CD8+ T cells. Immunol. Rev. 211, 81–92 (2006).

  24. 24.

    Control of immunity by the TNFR-related molecule OX40 (CD134). Annu. Rev. Immunol. 28, 57–78 (2010).

  25. 25.

    et al. Bioluminescence imaging allows measuring CD8 T cell function in the liver. Hepatology 51, 1430–1437 (2010).

  26. 26.

    et al. Transfer of HBV genomes using low doses of adenovirus vectors leads to persistent infection in immune competent mice. Gastroenterology 142, 1447–1450 (2012).

  27. 27.

    Revisiting the role of the granuloma in tuberculosis. Nat. Rev. Immunol. 12, 352–366 (2012).

  28. 28.

    et al. Th17 cells induce ectopic lymphoid follicles in central nervous system tissue inflammation. Immunity 35, 986–996 (2011).

  29. 29.

    et al. Dendritic cells control T cell tonic signaling required for responsiveness to foreign antigen. Proc. Natl. Acad. Sci. USA 107, 5931–5936 (2010).

  30. 30.

    et al. CpG-ODN-induced inflammation is sufficient to cause T-cell-mediated autoaggression against hepatocytes. Eur. J. Immunol. 32, 3628–3637 (2002).

  31. 31.

    et al. Toll-like receptor engagement converts T-cell autoreactivity into overt autoimmune disease. Nat. Med. 11, 138–145 (2005).

  32. 32.

    et al. Immunoprivileged status of the liver is controlled by Toll-like receptor 3 signaling. J. Clin. Invest. 116, 2456–2463 (2006).

  33. 33.

    et al. Inflammatory monocytes facilitate adaptive CD4 T cell responses during respiratory fungal infection. Cell Host Microbe 6, 470–481 (2009).

  34. 34.

    et al. TNF-induced target cell killing by CTL activated through cross-presentation. Cell Reports 2, 478–487 (2012).

  35. 35.

    et al. A lymphotoxin-driven pathway to hepatocellular carcinoma. Cancer Cell 16, 295–308 (2009).

  36. 36.

    et al. Endothelial CCR2 signaling induced by colon carcinoma cells enables extravasation via the JAK2-Stat5 and p38MAPK pathway. Cancer Cell 22, 91–105 (2012).

  37. 37.

    et al. CCR2+Ly-6Chi monocytes are crucial for the effector phase of autoimmunity in the central nervous system. Brain 132, 2487–2500 (2009).

  38. 38.

    , , & The use of spinning-disk confocal microscopy for the intravital analysis of platelet dynamics in response to systemic and local inflammation. PLoS ONE 6, e25109 (2011).

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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.).

Author information


  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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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.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Mathias Heikenwalder or Percy A Knolle.

Supplementary information

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    Supplementary Text and Figures

    Supplementary Figures 1–7


  1. 1.

    Supplementary Video 1

    Hepatic microvasculature and uptake of TLR9-L by sinusoidal cells.

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    Supplementary Video 2

    Hepatic microvasculature and uptake of TLR9-L by sinusoidal cells.

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    Supplementary Video 3

    Circulating CD11b+ cells adhere in sinusoids after TLR9-L application.

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    Supplementary Video 4

    Circulating CD11b+ cells adhere in sinusoids after TLR9-L application.

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    Supplementary Video 5

    CD11b+ cells form non-perfused structures, iMATEs.

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    Supplementary Video 6

    CD11b+ cells form non-perfused structures, iMATEs.

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    Supplementary Video 7

    CD11b+ cells form non-perfused structures, iMATEs.

  8. 8.

    Supplementary Video 8

    CD11b+ cells form non-perfused structures, iMATEs.

  9. 9.

    Supplementary Video 9

    CD8+ T cells migrate slowly within iMATEs.

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    Supplementary Video 10

    3D structures of iMATEs.

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    Supplementary Video 11

    3D structures of iMATEs.

  12. 12.

    Supplementary Video 12

    3D structures of iMATEs.

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