Deletion of IRF8-Dependent Dendritic Cells Abrogates Pro-Atherogenic 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-dependent DCs (lymphoid CD8α+ and their developmentally related non-lymphoid CD103+ DCs) in the induction of pro-atherogenic immune responses during high fat feeding.
Methods and Results: Using a fate mapping technique to track DCs originating from a DNGR1+ precursor (Clec9a+/creRosa+/EYFP mice), we first show that YFPhiMCD11chiMHCIIhi 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 towards T helper type 1 (Th1) cells, T follicular helper (Tfh) cells, and regulatory T cells (Tregs). 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 non-redundant role in the development of pro-atherogenic adaptive immunity.
- Received January 10, 2018.
- Revision received January 24, 2018.
- Accepted February 5, 2018.