Human Hematopoietic Stem Cell Engrafted IL-15 Transgenic NSG Mice Support Robust NK Cell Responses and Sustained HIV-1 Infection

Mice reconstituted with human immune systems are instrumental in the investigation of HIV-1 pathogenesis and therapeutics. Natural killer (NK) cells have long been recognized as a key mediator of innate anti-HIV responses. However, established humanized mouse models do not support robust human NK ce...

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Published inViruses Vol. 15; no. 2; p. 365
Main Authors Abeynaike, Shawn A, Huynh, Tridu R, Mehmood, Abeera, Kim, Teha, Frank, Kayla, Gao, Kefei, Zalfa, Cristina, Gandarilla, Angel, Shultz, Leonard, Paust, Silke
Format Journal Article
LanguageEnglish
Published Switzerland MDPI AG 27.01.2023
MDPI
Subjects
Animal models
Animal models in research
Animals
Antibodies
Antigens
Artificial chromosomes
Bone marrow
Cells
Cloning
Cord blood
Cytokines
Development and progression
Ethanol
Flow cytometry
Genes
Genetic aspects
Graft-versus-host reaction
Health aspects
Hematopoietic Stem Cells
HIV
HIV infection
HIV Infections - therapy
HIV Seropositivity
HIV-1
HIV-1 - genetics
Human immunodeficiency virus
humanized mice
Humans
IL-15
Immune response
Immune system
Immunodeficiency
Immunological research
immunotherapy
Infections
Interleukin 15
Interleukin 15 receptors
Interleukin-15 - genetics
Killer cells
Killer Cells, Natural
Kinases
Laboratories
Mice
Mice, Inbred NOD
Mice, SCID
Mice, Transgenic
Natural killer cells
NK cells
NSG
Physiological aspects
Transgenic mice
United States
Minneapolis Minnesota
United States > US
Chicago Illinois
HIV-1
IL-15
NK cells
NSG
humanized mice
immunotherapy
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Abstract Mice reconstituted with human immune systems are instrumental in the investigation of HIV-1 pathogenesis and therapeutics. Natural killer (NK) cells have long been recognized as a key mediator of innate anti-HIV responses. However, established humanized mouse models do not support robust human NK cell development from engrafted human hematopoietic stem cells (HSCs). A major obstacle to human NK cell reconstitution is the lack of human interleukin-15 (IL-15) signaling, as murine IL-15 is a poor stimulator of the human IL-15 receptor. Here, we demonstrate that immunodeficient NOD.Cg- /SzJ (NSG) mice expressing a transgene encoding human IL-15 (NSG-Tg(IL-15)) have physiological levels of human IL-15 and support long-term engraftment of human NK cells when transplanted with human umbilical-cord-blood-derived HSCs. These Hu-NSG-Tg(IL-15) mice demonstrate robust and long-term reconstitution with human immune cells, but do not develop graft-versus-host disease (GVHD), allowing for long-term studies of human NK cells. Finally, we show that these HSC engrafted mice can sustain HIV-1 infection, resulting in human NK cell responses in HIV-infected mice. We conclude that Hu-NSG-Tg(IL-15) mice are a robust novel model to study NK cell responses to HIV-1.
AbstractList Mice reconstituted with human immune systems are instrumental in the investigation of HIV-1 pathogenesis and therapeutics. Natural killer (NK) cells have long been recognized as a key mediator of innate anti-HIV responses. However, established humanized mouse models do not support robust human NK cell development from engrafted human hematopoietic stem cells (HSCs). A major obstacle to human NK cell reconstitution is the lack of human interleukin-15 (IL-15) signaling, as murine IL-15 is a poor stimulator of the human IL-15 receptor. Here, we demonstrate that immunodeficient NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ (NSG) mice expressing a transgene encoding human IL-15 (NSG-Tg(IL-15)) have physiological levels of human IL-15 and support long-term engraftment of human NK cells when transplanted with human umbilical-cord-blood-derived HSCs. These Hu-NSG-Tg(IL-15) mice demonstrate robust and long-term reconstitution with human immune cells, but do not develop graft-versus-host disease (GVHD), allowing for long-term studies of human NK cells. Finally, we show that these HSC engrafted mice can sustain HIV-1 infection, resulting in human NK cell responses in HIV-infected mice. We conclude that Hu-NSG-Tg(IL-15) mice are a robust novel model to study NK cell responses to HIV-1.
Mice reconstituted with human immune systems are instrumental in the investigation of HIV-1 pathogenesis and therapeutics. Natural killer (NK) cells have long been recognized as a key mediator of innate anti-HIV responses. However, established humanized mouse models do not support robust human NK cell development from engrafted human hematopoietic stem cells (HSCs). A major obstacle to human NK cell reconstitution is the lack of human interleukin-15 (IL-15) signaling, as murine IL-15 is a poor stimulator of the human IL-15 receptor. Here, we demonstrate that immunodeficient NOD.Cg- /SzJ (NSG) mice expressing a transgene encoding human IL-15 (NSG-Tg(IL-15)) have physiological levels of human IL-15 and support long-term engraftment of human NK cells when transplanted with human umbilical-cord-blood-derived HSCs. These Hu-NSG-Tg(IL-15) mice demonstrate robust and long-term reconstitution with human immune cells, but do not develop graft-versus-host disease (GVHD), allowing for long-term studies of human NK cells. Finally, we show that these HSC engrafted mice can sustain HIV-1 infection, resulting in human NK cell responses in HIV-infected mice. We conclude that Hu-NSG-Tg(IL-15) mice are a robust novel model to study NK cell responses to HIV-1.
Mice reconstituted with human immune systems are instrumental in the investigation of HIV-1 pathogenesis and therapeutics. Natural killer (NK) cells have long been recognized as a key mediator of innate anti-HIV responses. However, established humanized mouse models do not support robust human NK cell development from engrafted human hematopoietic stem cells (HSCs). A major obstacle to human NK cell reconstitution is the lack of human interleukin-15 (IL-15) signaling, as murine IL-15 is a poor stimulator of the human IL-15 receptor. Here, we demonstrate that immunodeficient NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ (NSG) mice expressing a transgene encoding human IL-15 (NSG-Tg(IL-15)) have physiological levels of human IL-15 and support long-term engraftment of human NK cells when transplanted with human umbilical-cord-blood-derived HSCs. These Hu-NSG-Tg(IL-15) mice demonstrate robust and long-term reconstitution with human immune cells, but do not develop graft-versus-host disease (GVHD), allowing for long-term studies of human NK cells. Finally, we show that these HSC engrafted mice can sustain HIV-1 infection, resulting in human NK cell responses in HIV-infected mice. We conclude that Hu-NSG-Tg(IL-15) mice are a robust novel model to study NK cell responses to HIV-1.Mice reconstituted with human immune systems are instrumental in the investigation of HIV-1 pathogenesis and therapeutics. Natural killer (NK) cells have long been recognized as a key mediator of innate anti-HIV responses. However, established humanized mouse models do not support robust human NK cell development from engrafted human hematopoietic stem cells (HSCs). A major obstacle to human NK cell reconstitution is the lack of human interleukin-15 (IL-15) signaling, as murine IL-15 is a poor stimulator of the human IL-15 receptor. Here, we demonstrate that immunodeficient NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ (NSG) mice expressing a transgene encoding human IL-15 (NSG-Tg(IL-15)) have physiological levels of human IL-15 and support long-term engraftment of human NK cells when transplanted with human umbilical-cord-blood-derived HSCs. These Hu-NSG-Tg(IL-15) mice demonstrate robust and long-term reconstitution with human immune cells, but do not develop graft-versus-host disease (GVHD), allowing for long-term studies of human NK cells. Finally, we show that these HSC engrafted mice can sustain HIV-1 infection, resulting in human NK cell responses in HIV-infected mice. We conclude that Hu-NSG-Tg(IL-15) mice are a robust novel model to study NK cell responses to HIV-1.
Mice reconstituted with human immune systems are instrumental in the investigation of HIV-1 pathogenesis and therapeutics. Natural killer (NK) cells have long been recognized as a key mediator of innate anti-HIV responses. However, established humanized mouse models do not support robust human NK cell development from engrafted human hematopoietic stem cells (HSCs). A major obstacle to human NK cell reconstitution is the lack of human interleukin-15 (IL-15) signaling, as murine IL-15 is a poor stimulator of the human IL-15 receptor. Here, we demonstrate that immunodeficient NOD.Cg- Prkdc scid Il2rg tm1Wjl /SzJ (NSG) mice expressing a transgene encoding human IL-15 (NSG-Tg(IL-15)) have physiological levels of human IL-15 and support long-term engraftment of human NK cells when transplanted with human umbilical-cord-blood-derived HSCs. These Hu-NSG-Tg(IL-15) mice demonstrate robust and long-term reconstitution with human immune cells, but do not develop graft-versus-host disease (GVHD), allowing for long-term studies of human NK cells. Finally, we show that these HSC engrafted mice can sustain HIV-1 infection, resulting in human NK cell responses in HIV-infected mice. We conclude that Hu-NSG-Tg(IL-15) mice are a robust novel model to study NK cell responses to HIV-1.
Audience Academic
Author Kim, Teha
Frank, Kayla
Abeynaike, Shawn A
Paust, Silke
Zalfa, Cristina
Shultz, Leonard
Gao, Kefei
Huynh, Tridu R
Mehmood, Abeera
Gandarilla, Angel
AuthorAffiliation 2 Scripps Research Translational Institute, La Jolla, CA 92037, USA
3 Division of Internal Medicine, Scripps Clinic/Scripps Green Hospital, La Jolla, CA 92037, USA
4 The Jackson Laboratory, Bar Harbor, ME 04609, USA
1 Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92037, USA
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BackLink https://www.ncbi.nlm.nih.gov/pubmed/36851579$$D View this record in MEDLINE/PubMed
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Issue 2
Keywords HIV-1
IL-15
NK cells
NSG
humanized mice
immunotherapy
Language English
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SSID ssj0066907
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Snippet Mice reconstituted with human immune systems are instrumental in the investigation of HIV-1 pathogenesis and therapeutics. Natural killer (NK) cells have long...
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StartPage 365
SubjectTerms Animal models
Animal models in research
Animals
Antibodies
Antigens
Artificial chromosomes
Bone marrow
Cells
Cloning
Cord blood
Cytokines
Development and progression
Ethanol
Flow cytometry
Genes
Genetic aspects
Graft-versus-host reaction
Health aspects
Hematopoietic Stem Cells
HIV
HIV infection
HIV Infections - therapy
HIV Seropositivity
HIV-1
HIV-1 - genetics
Human immunodeficiency virus
humanized mice
Humans
IL-15
Immune response
Immune system
Immunodeficiency
Immunological research
immunotherapy
Infections
Interleukin 15
Interleukin 15 receptors
Interleukin-15 - genetics
Killer cells
Killer Cells, Natural
Kinases
Laboratories
Mice
Mice, Inbred NOD
Mice, SCID
Mice, Transgenic
Natural killer cells
NK cells
NSG
Physiological aspects
Transgenic mice
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Title Human Hematopoietic Stem Cell Engrafted IL-15 Transgenic NSG Mice Support Robust NK Cell Responses and Sustained HIV-1 Infection
URI https://www.ncbi.nlm.nih.gov/pubmed/36851579
https://www.proquest.com/docview/2779702224
https://www.proquest.com/docview/2780767239
https://pubmed.ncbi.nlm.nih.gov/PMC9960100
https://doaj.org/article/8118595d335249e4852c48ee7118dd24
Volume 15
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