cDC1s Promote Atherosclerosis via Local Immunity and Are Targetable for Therapy.

Abstract

Atherosclerosis is characterized by immune cell accumulation in the arterial wall and adaptive CD4+ Th1 immunity contributes to atherosclerosis development. However, how conventional dendritic cells (cDCs) orchestrate this adaptive response remains controversial. This study unveils strategies for the gain and loss of function of cDCs to decipher their role in atherosclerosis induction in relation to adaptive T-cell immunity. We tested atherosclerosis in Ldlr-/- mice fed a high-cholesterol diet (HCD). Expansion of cDCs in vivo was achieved by overexpression of FLT3L (Fms-like tyrosine kinase 3 ligand), while the effect of ablation of conventional type 1 dendritic cells (cDC1s) in atherosclerosis was analyzed by grafting bone marrow from different mouse models of cDC1 depletion, including Xcr1Cre-DTA and Irf8Δ32 mice, into lethally irradiated Ldlr-/- recipients before HCD. CD3+ T-cell subsets were analyzed using flow cytometry or scRNA-seq. Nanoparticles loaded with dexamethasone and decorated with anti-CLEC9A antibody to target cDC1s were tested for immunotherapy. Expansion of dendritic cells in Ldlr-/- mice fed HCD for 8 weeks led to increased atherosclerotic lesion, which was prevented when Ldlr-/- mice were grafted before dendritic cell expansion with Xcr1Cre-DTA cDC1-depleted bone marrow compared with controls. Consistently, even in the absence of dendritic cell expansion, cDC1 deficiency prevented HCD-induced atherosclerosis. The scRNA-seq analysis of aortic CD3+ T cells in this experimental approach showed a local reduction in CD4+ Th1 and CD8+ IFN (interferon)-γ+ T cells in the absence of cDC1s compared with control mice. Mechanistically, stimulator of IFN genes in cDC1s was required for the proatherogenic function of cDC1s. As a potential cDC1-targeted immunotherapy for atherosclerosis, we generated lipid nanoparticles decorated with an anti-CLEC9A antibody to specifically target cDC1s. When loaded with the immunosuppressive drug dexamethasone, these nanoparticles promoted a reduction of the atherosclerotic lesion in Ldlr-/- mice fed HCD, correlating with decreased CD4+ Th1 and CD8+ IFN-γ+ T cells in the spleen. These immunosuppressive nanoparticles, however, did not impair antiviral response. Using state-of-the-art strategies, our results establish that cDC1s have a proatherogenic role in atherosclerosis by boosting CD4+ and CD8+ T-cell immunity and propose that cDC1s can be targeted with an immunosuppressive drug to decrease atherosclerosis progression.