Our data show that IL-27R signaling is critical in limiting both early and late stages of atherosclerosis by controlling myeloid cell accumulation (via regulation of adhesion molecule and chemokine expression), and regulating myeloid cells activation and antigen presentation (by limiting MHCII expression and cytokine production) in the aortas, subsequently affecting CD4+ T cells activation and atherosclerosis progression. Here, CD4 is linked to atherosclerosis.