Background: Our investigations have suggested that Cramp, the mouse homolog of human cathelicidin protein hCAP-18, is a potential self-antigen in atherosclerosis. In this study, we immunized ApoE(-/-) mice with Cramp using two different doses to address the potential role of self-antigen dose in auto-reactive immune responses and effects on atherosclerosis.Methods and Results: Cramp peptide was formulated with Adjuphos and MPLA as adjuvant. Mice were immunized at a dose of 20μg or 100μg at 7, 10, and 12 weeks of age. Adjuvant alone or PBS treated mice served as controls. At 13 weeks of age, mice were fed high fat diet for 12 weeks until euthanasia. The 20μg dose significantly reduced aortic plaque size whereas 100μg exacerbated the disease with increased neutrophils and aortic sinus plaque size (Table). For mechanistic studies, splenocytes from ApoE(-/-) FoxP3 mice euthanized one week after last immunization were stimulated with Cramp for 24 hours. Compared to PBS and Adjuvant controls the 20μg dose resulted in increased splenic CD8+ Central Memory T cells (7.2±1.2 vs 6.8±1.5 and 9.2±2.3% respectively; N=11-14 each; P<0.05) and increased CD8+ T cell degranulation assessed by CD107a staining (0.9±0.1 vs 0.7±0.1 and 0.5±0.1%, respectively; N=4 each, P<0.05) with reduced CD11b+CD11c+ conventional dendritic cells (cDCs; Table). The 100ug immunization dose compared to PBS and Adjuvant controls increased CD4+ Effector Memory [EM] (14.9±5.7 vs 10.9±1.3 and 9.1±0.9%, respectively; 10-16 each, P<0.05) and CD8+ EM T cells (5.2±0.7 vs 3.7±0.6 and 3.6±1.6%, respectively; N=10-16 each, P<0.05), along with increased CD11b+ cDCs (Table). No differences were found in Treg populations.Conclusion: Our results identified Cramp as a potential self-antigen involved in the auto-reactive immune response to atherosclerosis in ApoE(-/-) mouse. The study underscores the effects of self-antigen dose in immune auto-reactivity and atherosclerosis.