Hypercholesterolemic mice lacking factors required for activation of CD4+effector T cells are characterized by reduced development of atherosclerosis.Against this background it has been assumed that atherosclerosis involvesa loss of tolerance against modified self-antigens generated in response tohypercholesterolemia and that presentation of such antigens on MHC class IImolecules lead to activation of pro-inflammatory Th1 cells. To test this possibilitywe investigated atherosclerosis development in ApoE−/− mice deficient forMHC class II (ApoE−/−MHCII−/−). As expected ApoE−/−MHCII−/− mice hadreduced levels of CD4+ T cells, low levels of IgG and IgM, as well asof Th1 and Th2 cytokines in plasma. CD115+ monocytes were reduced inspleen as well as the plasma levels of TNF-a, IL-1b and IL-6 indicatingreduced systemic inflammation. In spite of this, ApoE−/−MHCII−/− mice hadsignificantly more atherosclerosis as assessed both by en face Oil Red Ostaining of the aorta (4.7±2.9% versus 1.9±1.3%; P < 0.01) and cross-sectionalarea of subvalvular lesions (7.7±2.2x105 versus 4.6±2.8x105 mm2 ; P < 0.05).Moreover, macrophage accumulation in lesions was significantly increased(44.8±8.0% versus 24.8±7.8% MOMA-2 stained area; P < 0.001). The presentobservations unexpectedly show that the net effect of MHC class II-dependentantigen presentation in atherosclerosis is athero-protective and suggest thatthis effect occurs locally in the arterial wall rather than at the systemic level.