Lack of Ability to Present Antigens on Major Histocompatibility Complex Class II Molecules Aggravates Atherosclerosis in ApoE-/- Mice

Background: Hypercholesterolemic mice lacking factors required for activation of CD4(+) T cells are characterized by reduced development of atherosclerosis. Consequently, it has been assumed that atherosclerosis involves loss of tolerance against modified self-antigens generated in response to hypercholesterolemia and that presentation of such antigens on major histocompatibility complex class II (MHCII) leads to activation of proatherogenic Th1 cells. In this study, we wanted to determine the role of antigen presentation on MHCII in atherosclerosis development. Methods: Apolipoprotein E (ApoE(-/-)) mice deficient for MHCII (ApoE(-/-)MHCII(-/-)) were used to study the role of MHCII in atherosclerosis development. Results: Compared with ApoE(-/-) mice, ApoE(-/-)MHCII(-/-) mice had reduced levels of CD4(+) T cells, immunoglobulin G and M levels, and Th1 and Th2 cytokines in plasma. CD8(+) T cells were increased and regulatory T cells were reduced both in spleen and in lesions of ApoE(-/-)MHCII(-/-) mice. Decreased plasma levels of inflammatory cytokines in ApoE(-/-)MHCII(-/-) mice indicated reduced systemic inflammation. Despite this, ApoE(-/-)MHCII(-/-) mice had significantly more atherosclerosis as assessed by en face Oil Red O staining of the aorta (4.7 +/- 2.9% versus 1.9 +/- 1.3%; P<0.01) and cross-sectional area of subvalvular lesions (7.7 +/- 2.2x10(5) mu m(2) versus 4.6 +/- 2.8x10(5) mu m(2); P<0.05). Cell transfer and blocking antibody studies suggested that loss of regulatory T cells is the most important cause of aggravated atherosclerosis in ApoE(-/-)MHCII(-/-) mice. Conclusions: Our observations demonstrate that antigen presentation on MHCII has important protective functions in atherosclerosis and that this is primarily the result of activation of regulatory T cells. These findings have implications for understanding the possible risks and benefits of immunosuppressive therapy in patients with cardiovascular disease.