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

Area of Science:

• Immunology
• Virology
• Transplantation

Background:

• Humanized mouse models are crucial for studying HIV-1 pathogenesis and treatment.
• Natural killer (NK) cells are key innate immune cells involved in anti-HIV responses.
• Existing models poorly support human NK cell development due to inadequate human IL-15 signaling.

Purpose of the Study:

• To develop an improved humanized mouse model for studying human NK cell function.
• To overcome the limitation of poor human NK cell reconstitution in current models.
• To investigate NK cell responses in the context of HIV-1 infection.

Main Methods:

• Utilized immunodeficient NOD.Cg-Prkdc/SzJ (NSG) mice engineered to express human IL-15 (NSG-Tg(IL-15)).
• Transplanted human umbilical cord blood-derived hematopoietic stem cells (HSCs) into these mice.
• Assessed long-term engraftment of human immune cells, including NK cells, and susceptibility to HIV-1 infection.
• Monitored for graft-versus-host disease (GVHD).

Main Results:

• NSG-Tg(IL-15) mice exhibited physiological levels of human IL-15.
• Successful long-term engraftment and development of human NK cells from HSCs were achieved.
• The model supported robust reconstitution of human immune cells without developing GVHD.
• Engrafted mice sustained HIV-1 infection, allowing observation of human NK cell responses.

Conclusions:

• Hu-NSG-Tg(IL-15) mice represent a significant advancement in humanized models for immunology research.
• This novel model overcomes critical limitations in supporting human NK cell development.
• It provides a powerful platform for long-term investigation of NK cell immunity against HIV-1.