Abstract Body: Atherosclerotic cardiovascular disease commonly manifests itself in middle-aged humans. Apolipoprotein (apo) B immunity has been implicated in the disease process, but its effects in middle-aged mice have not been explored. Two T cell receptor transgenic mouse strains with T cells reactive against apoB (BT1 and BT3) were crossbred with human APOB100-transgenic Ldlr-/- (HuBL) mice, and atherosclerosis was evaluated. In 52-week-old BT1xHuBL mice, a lower atherosclerotic burden was observed in the aorta, mirrored by reduced plasma cholesterol compared to matched HuBL controls. BT3xHuBL mice also exhibited a decrease in aortic atherosclerosis; however, no reduction in plasma cholesterol levels was noted. Instead, type 1 regulatory T cell responses with interleukin (IL)-10 production were mounted. This response was specifically associated with reduced collagen content and a lower stability index of the atherosclerotic lesions. In human carotid plaques, IL10 levels were negatively correlated with collagen expression, and IL-10 was found to inhibit collagen production in vascular smooth muscle cells. Together, atheroprotective apoB immunity elicits two distinct pathways: lipid-lowering immune reactions and local anti-inflammatory IL-10 production. Since the latter is associated with decreased plaque stability and cardiovascular events, treatments aimed at increasing IL-10 signaling over extended periods to reduce vascular inflammation need reconsideration.