Abstract Systemic lupus erythematosus (SLE) is a chronic and complex autoimmune disease that can cause multi-organ damages. Patients with SLE often have higher risk for heart disease, with poorly defined underlying mechanisms. We generated a Cx3cr1-deficient MRL/lprlupus-prone mouse which exhibits a distinct phenotype of exacerbated glomerulonephritis. Upon feeding with a high-fat diet, Cx3cr1−/−MRL/lprmice developed significantly more atherosclerotic plaques that were promoted by Cx3cr1deficiency-mediated activation of Ly6C ++monocytes. The activated monocytes expressed ICOS-L that interacted with ICOS-expressing follicular T helper cells, which in turn facilitated a germinal center reaction to produce more autoantibodies. Through a positive feedback mechanism, the increased circulatory autoantibodies further promoted the activation of Ly6C-expressing monocytes and their display of ICOS-L. Together, we uncovered a novel, Cx3cr1deficiency-mediated pathogenic mechanism contributing to SLE-associated atherosclerosis in MRL/lprmice. The results of these studies will lead to the identification of new therapeutic targets for SLE patients at risk of developing cardiovascular disease.