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 ( Clec9a +/cre Rosa +/EYFP mice), we first show that YFPhi CD11chi MHCIIhi (major histocompatibility complex class II) DCs are present in the atherosclerotic aorta of low-density lipoprotein receptor-deficient ( Ldlr -/- ) mice and are CD11b- CD103+ IRF8hi . Restricted deletion of IRF8 in DCs ( Irf8 flox/flox Cd11c Cre ) reduces the accumulation of CD11chi MHCIIhi DCs in the aorta without affecting CD11b+ CD103- DCs or macrophages but completely abolishes the accumulation of aortic CD11b- CD103+ 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.