Humanized mouse model supports development, function, and tissue residency of human natural killer cells

Dietmar Herndler-Brandstetter, Liang Shan, Yi Yao, Carmen Stecher, Valerie Plajer, Melanie Lietzenmayer, Till Strowig, Marcel R. De Zoete, Noah W. Palm, Jie Chen, Catherine A. Blish, Davor Frleta, Cagan Gurer, Lynn E. Macdonald, Andrew J. Murphy, George D. Yancopoulos, Ruth R. Montgomery, Richard A. Flavell

Research output: Contribution to journalArticle

47 Scopus citations

Abstract

Immunodeficient mice reconstituted with a human immune system represent a promising tool for translational research as they may allow modeling and therapy of human diseases in vivo. However, insufficient development and function of human natural killer (NK) cells and T cell subsets limit the applicability of humanized mice for studying cancer biology and therapy. Here, we describe a human interleukin 15 (IL15) and human signal regulatory protein alpha (SIRPA) knock-in mouse on a Rag2−/− Il2rg−/− background (SRG-15). Transplantation of human hematopoietic stem and progenitor cells into SRG-15 mice dramatically improved the development and functional maturation of circulating and tissue-resident human NK and CD8+ T cells and promoted the development of tissue-resident innate lymphoid cell (ILC) subsets. Profiling of human NK cell subsets by mass cytometry revealed a highly similar expression pattern of killer inhibitory receptors and other candidate molecules in NK cell subpopulations between SRG-15 mice and humans. In contrast to nonobese diabetic severe combined immunodeficient Il2rg−/− (NSG) mice, human NK cells in SRG-15 mice did not require preactivation but infiltrated a Burkitt’s lymphoma xenograft and efficiently inhibited tumor growth following treatment with the therapeutic antibody rituximab. Our humanized mouse model may thus be useful for preclinical testing of novel human NK cell-targeted and combinatory cancer immunotherapies and for studying how they elicit human antitumor immune responses in vivo.

Original languageEnglish
Pages (from-to)E9626-E9634
JournalProceedings of the National Academy of Sciences of the United States of America
Volume114
Issue number45
DOIs
StatePublished - Nov 7 2017

Keywords

  • Cancer immunotherapy
  • Humanized mice
  • IL-15
  • ILC
  • NK cells

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    Herndler-Brandstetter, D., Shan, L., Yao, Y., Stecher, C., Plajer, V., Lietzenmayer, M., Strowig, T., De Zoete, M. R., Palm, N. W., Chen, J., Blish, C. A., Frleta, D., Gurer, C., Macdonald, L. E., Murphy, A. J., Yancopoulos, G. D., Montgomery, R. R., & Flavell, R. A. (2017). Humanized mouse model supports development, function, and tissue residency of human natural killer cells. Proceedings of the National Academy of Sciences of the United States of America, 114(45), E9626-E9634. https://doi.org/10.1073/pnas.1705301114