Journal
CIRCULATION RESEARCH
Volume 122, Issue 6, Pages 813-+Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/CIRCRESAHA.118.312713
Keywords
atherosclerosis; dendritic cells; immune system; lymphocytes; mice
Funding
- British Heart Foundation
- European Research Council
- European HEALTH 2013.1.3-3 programme
- British Heart Foundation [RG/15/11/31593] Funding Source: researchfish
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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 CD8 alpha(+) 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 YFP(hi)CD11(chi)MHCII(hi) (major histocompatibility complex class II) DCs are present in the atherosclerotic aorta of low-density lipoprotein receptor-deficient (Ldlr(-/-)) mice and are CD11b-CD103(+) IRF8(hi). Restricted deletion of IRF8 in DCs (Irf8(flox/flox)Cd11c(Cre)) reduces the accumulation of CD11c(hi)MHCII(hi) DCs in the aorta without affecting CD11b(+)CD103(-)DCs or macrophages but completely abolishes the accumulation of aortic CD11b-CD103(+)DCs. Lymphoid CD8 alpha(+) 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.
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