Hypercholesterolemia induces T cell expansion in humanized immune mice

Area of Science:

• Immunology
• Cardiovascular Disease Research
• Humanized Mouse Models

Background:

• Hypercholesterolemia is linked to immune system stimulation, potentially promoting atherosclerosis and inflammatory conditions.
• Previous research used mouse models with immune systems differing from humans and extreme hypercholesterolemia.
• Humanized mice offer a more relevant model to study human immune responses in hypercholesterolemia.

Purpose of the Study:

• To investigate the effects of moderate hypercholesterolemia on the human adaptive immune system in vivo.
• To establish a more accurate model for studying human immune responses to elevated cholesterol.

Main Methods:

• Utilized human immune system-reconstituted mice (hu-mice).
• Induced moderate hypercholesterolemia using adeno-associated virus 8-proprotein convertase subtilisin/kexin type 9 (AAV8-PCSK9) and a Western-type diet (WD).
• Analyzed T cell populations and inflammatory responses in blood, spleen, lung, and liver.

Main Results:

• PCSK9-WD hu-mice exhibited moderate hypercholesterolemia and a high proportion of human T cells.
• Developed significant T cell-mediated inflammatory responses in the lung and liver.
• Showed elevated effector memory human CD4+ and CD8+ T cells, with reduced regulatory T cells.

Conclusions:

• Moderately high plasma cholesterol disrupts human T cell homeostasis in vivo.
• This disruption may exacerbate atherosclerosis and contribute to other T cell-mediated inflammatory diseases.
• Humanized mice treated with AAV8-PCSK9 and WD provide a valuable model for studying cholesterol's impact on human immunity.