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Development and function of human innate immune cells in a humanized mouse model

Nature Biotechnology volume 32, pages 364–372 (2014)Cite this article

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A Corrigendum to this article was published on 08 December 2017

This article has been updated

Abstract

Mice repopulated with human hematopoietic cells are a powerful tool for the study of human hematopoiesis and immune function in vivo. However, existing humanized mouse models cannot support development of human innate immune cells, including myeloid cells and natural killer (NK) cells. Here we describe two mouse strains called MITRG and MISTRG, in which human versions of four genes encoding cytokines important for innate immune cell development are knocked into their respective mouse loci. The human cytokines support the development and function of monocytes, macrophages and NK cells derived from human fetal liver or adult CD34+ progenitor cells injected into the mice. Human macrophages infiltrated a human tumor xenograft in MITRG and MISTRG mice in a manner resembling that observed in tumors obtained from human patients. This humanized mouse model may be used to model the human immune system in scenarios of health and pathology, and may enable evaluation of therapeutic candidates in an in vivo setting relevant to human physiology.

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Figure 1: Efficient engraftment of human hematopoietic cells in MITRG and MISTRG mice.
Figure 2: MITRG and MISTRG mice support efficient myeloid cell development in lymphoid and nonlymphoid tissues.
Figure 3: Monocytes in MITRG and MISTRG mice are functional.
Figure 4: Human NK cells develop efficiently in MISTRG mice.
Figure 5: Human NK cells in MITRSG mice are fully functional.
Figure 6: Infiltration and growth of a tumor in MISTRG mice.

Change history

  • 08 November 2017

    In the version of this article initially published, the cells labeled Me290 were Me275 cells. Both Me275 and Me290 are human metastatic HLA-A201+ melanoma cell lines, and both of them were obtained from the Ludwig Cancer Institute. Therefore, the mislabeling does not affect the conclusions of the paper. The error has been corrected in the HTML and PDF versions of the article.

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Acknowledgements

We thank G. Yancopoulos, D. Valenzuela, A. Murphy and W. Auerbach at Regeneron Pharmaceuticals who generated, in collaboration with our groups, the individual knock-in alleles combined in MISTRG, J. Alderman for managerial support, A.M. Franco, P. Ranney, C. Weibel, S. Patel and M. Santhanakrishnan for technical assistance, G. Lyon for cell sorting and C. Lieber for manuscript submission. This work was supported by the Bill and Melinda Gates Foundation and US National Institutes of Health CA156689 (to R.A.F. and M.G.M.), CA129350, CA84512, CA140602 (to A.K.P.); the University of Zurich Clinical Research Program (to M.G.M.); the Juvenile Diabetes Research Foundation and the Connecticut Stem Cell Research Grants Program (to R.A.F.); the Baylor Health Care System Foundation (to A.K.P.); and an Institutional Research Grant 58-012-54 from the American Cancer Society (to S.H.). T.S. was supported by the Leukemia and Lymphoma Society. The Me275 cell line was established at the Ludwig Cancer Institute in Lausanne.

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Author notes

  1. Till Strowig

    Present address: Present address: Helmholtz Centre for Infection Research, Braunschweig, Germany.,

  2. Anthony Rongvaux and Tim Willinger: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Immunobiology, Yale University, New Haven, Connecticut, USA

    Anthony Rongvaux, Tim Willinger, Till Strowig, Sofia V Gearty & Richard A Flavell

  2. Baylor Institute for Immunology Research, Dallas, Texas, USA

    Jan Martinek, Florentina Marches & A Karolina Palucka

  3. Biomedical studies program, Baylor University, Waco, Texas, USA

    Jan Martinek

  4. Department of Laboratory Medicine, Yale University, New Haven, Connecticut, USA

    Lino L Teichmann

  5. Department of Medicine III, University Hospital Bonn, Bonn, Germany

    Lino L Teichmann

  6. Division of Hematology, University Hospital Zurich, Zurich, Switzerland

    Yasuyuki Saito & Markus G Manz

  7. Department of Internal Medicine and Yale Comprehensive Cancer Center, Section of Hematology, Yale University, New Haven, Connecticut, USA

    Stephanie Halene

  8. Howard Hughes Medical Institute, Yale University, New Haven, Connecticut, USA

    Richard A Flavell

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Contributions

A.R., T.W. and J.M. designed and performed experiments and analyzed result. T.S., S.V.G., L.L.T., Y.S. and F.M. performed experiments. S.H. provided reagents. A.K.P. designed experiments and analyzed results. M.G.M. and R.A.F. conceived the project and supervised its participants and interpreted its results. A.R., T.W., A.K.P., M.G.M. and R.A.F. wrote the manuscript.

Corresponding authors

Correspondence to Markus G Manz or Richard A Flavell.

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The authors declare no competing financial interests.

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Rongvaux, A., Willinger, T., Martinek, J. et al. Development and function of human innate immune cells in a humanized mouse model. Nat Biotechnol 32, 364–372 (2014). https://doi.org/10.1038/nbt.2858

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