Deletion of IRF8 (Interferon Regulatory Factor 8)-Dependent Dendritic Cells Abrogates Proatherogenic Adaptive ImmunityNovelty and Significance
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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+/creRosa+/EYFP mice), we first show that YFPhiCD11chiMHCIIhi (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 (Irf8flox/floxCd11cCre) reduces the accumulation of CD11chiMHCIIhi 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.
- Received January 10, 2018.
- Revision received January 24, 2018.
- Accepted February 5, 2018.
- © 2018 American Heart Association, Inc.