Proatherogenic conditions promote autoimmune Th17 responses in vivo (P4136)

Abstract

Abstract Although patients with atherosclerosis have a higher incidence of systemic autoimmune diseases, the relationship between proatherogenic factors and autoimmune T cell responses is poorly understood. Mice lacking both LDL receptor and apolipoprotein B mRNA editing enzyme (Ldlr-/-Apobec1-/-; LDb) are hyperlipidemic and prone to atherosclerosis. Here, we show that LDb mice exhibit increased IL-17 in circulation as well as in the aortic sinus area, which was attributed to a preferential enhancement of Th17 cells in the secondary lymphoid organs. In addition, the environment within LDb mice was substantially favorable for the Th17 polarization of auto-reactive CD4+ T cells during homeostatic proliferation. In vitro, the addition of oxidized LDL, but not native LDL, promoted dendritic cell-mediated Th17 polarization by triggering IL-6 and IL-1 in a MyD88-dependent fashion. Furthermore, myelin oligodendrocyte glycoprotein (MOG)-reactive CD4+ T cells expanded in the presence of oxidized LDL expressed increased levels of Th17 signature genes, and induced more profound experimental autoimmune encephalitomyelitis (EAE) when transferred into naïve mice. Our findings demonstrate that proatherogenic factors induce the polarization and functional maturation of autoimmune Th17 cells, which may be critical for the pathogenesis of atherosclerosis and other related autoimmune diseases.