3 years ago

Humanized mouse model supports development, function, and tissue residency of human natural killer cells [Immunology and Inflammation]

Humanized mouse model supports development, function, and tissue residency of human natural killer cells [Immunology and Inflammation]
Richard A. Flavell, Marcel R. de Zoete, Noah W. Palm, Valerie Plajer, Carmen Stecher, Lynn E. Macdonald, Liang Shan, Yi Yao, Cagan Gurer, Catherine A. Blish, Dietmar Herndler-Brandstetter, Ruth R. Montgomery, George D. Yancopoulos, Jie Chen, Till Strowig, Melanie Lietzenmayer, Andrew J. Murphy, Davor Frleta

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.

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