Tim-1 mucin domain-mutant mice display exacerbated atherosclerosis

Abstract

Increasing evidence has shown that immune checkpoint molecules of

the T-cell immunoglobulin and mucin domain (TIM) family are associated with diverse

physiologic and pathologic pro- cesses. Previous studies investigating TIM-1 in atherosclerosis

using anti- TIM-1 antibodies have yielded contradictory results. We thus aimed to investigate atherosclerosis development in TIM-1 deficient mice. In this study, mice with a specific loss of the TIM-1 mucin- domain (TIM-1Dmucin) were used. TIM-1Dmucin mice and control WT (C57/ Bl6) mice received a single i.v. injection of 5x1011 rAAV8-D377Y-mPCSK9 vector genomes and were fed a Western-type diet for 13 weeks. TIM-1Dmucin mice developed significantly larger lesions in the aortic root and arch compared to WT mice. These lesions were composed of significantly more macrophages and showed a trend towards a larger necrotic core. The exacerbated atherosclerosis in TIM-1Dmucin mice was associated with a significant loss of IL-10+ B cells and regulatory B cell subsets compared to WT mice. TIM-1Dmucin mice also showed an increase in splenic and circulating leukocytes compared to WT mice, which was caused by an increase in B and CD4+ T cells in the spleen, while no specific leukocyte population was changed in the circulation. TIM- 1Dmucin mice also displayed a dramatic reduction in Th2-associated immune response compared to controls but no changes in humoral immune response. In summary, TIM-1Dmucin mice displayed a profound impairment in IL-10+ B cells and an imbalance in the Th1/Th2 ratio, which associated with exacerbated atherosclerosis.