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IL-12 initiates tumor rejection via lymphoid tissue–inducer cells bearing the natural cytotoxicity receptor NKp46

Nature Immunology volume 11, pages 1030–1038 (2010)Cite this article

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Abstract

The potent tumoricidal activity of interleukin 12 (IL-12) is thought to be mediated by the activation and polarization of natural killer (NK) cells and T helper type 1 (TH1) cells, respectively. By systematic analysis of the IL-12-induced immune response to subcutaneous melanoma (B16), we found that tumor suppression was mediated independently of T lymphocytes or NK cells. IL-12 initiated local antitumor immunity by stimulating a subset of NKp46+ lymphoid tissue–inducer (LTi) cells dependent on the transcription factor RORγt. The presence of these NKp46+ LTi cells induced upregulation of adhesion molecules in the tumor vasculature and resulted in more leukocyte invasion. Thus, this innate cell type is responsive to IL-12 and is a powerful mediator of tumor suppression.

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Figure 1: IL-12 acts locally in a paracrine manner.
Figure 2: IL-12 elicits the recruitment of leukocytes into the tumor mass.
Figure 3: IL-12-mediated repression of subcutaneous tumor acts independently of T cells, B cells, NKT cells and cNK cells.
Figure 4: Adoptive transfer of leukocytes bearing IL-12R reestablishes tumor suppression in IL12rb2−/− mice.
Figure 5: IL-12 induces the invasion of NKp46+ cells into the tumor mass.
Figure 6: NKp46+ LTi cells suppress tumor growth in an IL-12R- and RORγt-dependent way.
Figure 7: The role of effector cytokines in IL-12-mediated tumor suppression.
Figure 8: LTi cells alter the tumor microvasculature.

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Acknowledgements

We thank S. Bulfone-Paus (Research Center Borstel) for Il15ra−/− mice; A. Diefenbach (University Hospital Freiburg) for Rorc-eYFP mice; Y. Iwakura (University of Tokyo) for Il17a−/− mice; J.C. Renauld (Ludwig Institute Brussels) for Il22−/− mice; R. Zinkernagel (University Hospital of Zurich) for anti-CD4 and anti-CD8; M. Kopf and A. Diefenbach for discussions; and V. Tosevski, S. Burkhard, B. Sobotka, V. Wortmann and S. Behnke for technical assistance. Supported by the Swiss National Science Foundation (B.B.), the Swiss Cancer League (B.B.), the Center for Neurosciences Zurich (M.E.) and the Marie Heim-Vögtlin Programme (E.S.).

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  1. Elisabeth Saller

    Present address: Present address: Institut für Medizinische & Molekulare Diagnostik, Zurich, Switzerland.,

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  1. Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland

    Maya Eisenring, Johannes vom Berg, Elisabeth Saller & Burkhard Becher

  2. Department of Pathology, Institute of Clinical Pathology, University Hospital of Zurich, Zurich, Switzerland

    Glen Kristiansen

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M.E. and E.S. designed and did the experiments and analyzed the data; J.v.B. did experiments and analyzed the histology; G.K. provided advice for the histological analysis; B.B. designed the experiments, supervised and funded the study; B.B. and M.E. wrote the report.

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Correspondence to Burkhard Becher.

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Eisenring, M., vom Berg, J., Kristiansen, G. et al. IL-12 initiates tumor rejection via lymphoid tissue–inducer cells bearing the natural cytotoxicity receptor NKp46. Nat Immunol 11, 1030–1038 (2010). https://doi.org/10.1038/ni.1947

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