Humanized mouse model supports development, function, and tissue residency of human natural killer cells
Herndler-Brandstetter, D., Shan, L., Yao, Y., Stecher, C., Plajer, V., Lietzenmayer, M., … 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. doi:10.1073/pnas.1705301114
Proceedings of the National Academy of Sciences of the United States of America
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.
Published under the PNAS license.
Medical Subject Headings
Animals; CD8-Positive T-Lymphocytes; Disease Models, Animal; Humans; Immunity, Innate; Interleukin Receptor Common gamma Subunit; Interleukin-15; Killer Cells, Natural; Lymphocytes; Mice; Mice, SCID; Receptors, Immunologic; Rituximab