Deletion of IRF8 (Interferon Regulatory Factor 8)-Dependent Dendritic Cells Abrogates Proatherogenic Adaptive Immunity

RATIONALE:Despite an established role for adaptive immune responses in atherosclerosis, the contribution of dendritic cells (DCs) and their various subsets is still poorly understood. OBJECTIVE:Here, we address the role of IRF8 (interferon regulatory factor 8)-dependent DCs (lymphoid CD8α and their developmentally related nonlymphoid CD103 DCs) in the induction of proatherogenic immune responses during high fat feeding. METHODS AND RESULTS:Using a fate-mapping technique to track DCs originating from a DNGR1 (dendritic cell natural killer lectin group receptor 1) precursor (Clec9aRosa mice), we first show that YFPCD11cMHCII (major histocompatibility complex class II) DCs are present in the atherosclerotic aorta of low-density lipoprotein receptor–deficient (Ldlr) mice and are CD11bCD103IRF8. Restricted deletion of IRF8 in DCs (Irf8Cd11c) reduces the accumulation of CD11cMHCII DCs in the aorta without affecting CD11bCD103 DCs or macrophages but completely abolishes the accumulation of aortic CD11bCD103 DCs. Lymphoid CD8α DCs are also deleted. This is associated with a significant reduction of aortic T-cell accumulation and a marked reduction of high-fat diet–induced systemic T-cell priming, activation, and differentiation toward T helper type 1 cells, T follicular helper cells, and regulatory T cells. As a consequence, B-cell activation and germinal center responses to high-fat diet are also markedly reduced. IRF8 deletion in DCs significantly reduces the development of atherosclerosis, predominantly in the aortic sinus, despite a modest increase in total plasma cholesterol levels. CONCLUSIONS:IRF8 expression in DCs plays a nonredundant role in the development of proatherogenic adaptive immunity.