Tim-1 mucin domain-mutant mice display exacerbated atherosclerosis

Area of Science:

• Immunology
• Cardiovascular Research
• Molecular Biology

Background:

• Immune checkpoint molecules, including the T-cell immunoglobulin and mucin domain (Tim) family, are increasingly implicated in various physiological and pathological processes.
• Previous research on the role of Tim-1 in atherosclerosis has produced conflicting findings due to the use of anti-Tim-1 antibodies.
• This study investigates atherosclerosis development in mice with a specific deficiency in the Tim-1 mucin domain.

Purpose of the Study:

• To elucidate the role of the Tim-1 mucin domain in the development of atherosclerosis.
• To analyze the impact of Tim-1 mucin domain deficiency on immune cell populations and responses in an atherosclerosis model.
• To understand the relationship between Tim-1 mucin domain expression and the progression of atherosclerotic lesions.

Main Methods:

• Atherosclerosis was induced in Tim-1 mucin-domain deficient (Tim-1^Δmucin) mice and wild-type (WT) C57BL/6 mice.
• Mice received a single injection of a recombinant adeno-associated virus encoding murine Pcsk9 (rAAV2/8-D377Y-mPcsk9).
• A Western-type diet was administered for 13 weeks to promote atherosclerosis development.

Main Results:

• Tim-1^Δmucin mice exhibited significantly larger aortic root lesions compared to WT mice.
• These lesions contained more macrophages and a trend towards larger necrotic cores in Tim-1^Δmucin mice.
• A significant reduction in IL-10⁺ B cells and regulatory B cell subsets, alongside an increase in pro-atherogenic splenic follicular B cells, was observed in Tim-1^Δmucin mice. A decrease in Th2 immune response was noted, without affecting humoral immunity.

Conclusions:

• Mice deficient in the Tim-1 mucin domain showed impaired IL-10⁺ B cell function.
• An imbalance in the Th1/Th2 immune ratio was observed in Tim-1^Δmucin mice.
• These immune alterations were associated with exacerbated atherosclerosis, highlighting the protective role of the Tim-1 mucin domain in this condition.