Xcr1+ type 1 conventional dendritic cells are essential mediators for atherosclerosis progression
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Curated by eLife
eLife Assessment
This manuscript by Li, Lu et al., presents important findings on the role of cDC1 in atherosclerosis and their influence on the adaptive immune system. Using Xcr1Cre-Gfp Rosa26LSL-DTA ApoE-/- mouse models, these data convincingly reveal an unexpected, non-redundant role of the XCL1-XCR1 axis in mediating cDC1 contributions to atherosclerosis.
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Abstract
Abstract
Background
Atherosclerosis is characterized by lipid accumulation within plaques, leading to foam cell formation and an inflammatory response within the aortic lesions. Lipid disorders have been extensively investigated, however the cellular and molecular mechanisms that trigger the inflammatory response in atherosclerotic plaques remain far from being fully understood. Xcr1+ cDC1 cells are newly identified antigen-presenting cells in activating immune cells. However, the role of cDC1 cells in the development of atherosclerosis remains highly controversial.
Methods and Results
We first confirmed the presence of cDC1 within human atherosclerotic plaques and discovered a significant association between the increasing cDC1 numbers and atherosclerosis progression in mice. Subsequently, we established Xcr1Cre-Gfp Rosa26LSL-DTA ApoE−/− mice, a novel and complex genetic model, in which cDC1 was selectively depleted in vivo during atherosclerosis development. Intriguingly, we observed a notable reduction in atherosclerotic lesions in hyperlipidemic mice, alongside suppressed T cell activation of both CD4+ and CD8+ subsets in the aortic plaques. Notably, aortic macrophages and serum lipid levels were not significantly changed in the cDC1-depleted mice. Single-cell RNA sequencing revealed heterogeneity of Xcr1+ cDC1 cells across the aorta and lymphoid organs under hyperlipidemic conditions. As Xcr1 is the sole receptor for Xcl1, we next explored to target Xcr1+ cDC1 cells via Xcl1 by establishing Xcl1 and ApoE deficient mice. Our data indicate that atherosclerotic lesions mediated by cDC1 are dependent on Xcl1.
Conclusions
Our results reveal crucial roles of cDC1 in atherosclerosis progression and provide insights into the development of immunotherapies by targeting cDC1 through Xcl1.
Article activity feed
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eLife Assessment
This manuscript by Li, Lu et al., presents important findings on the role of cDC1 in atherosclerosis and their influence on the adaptive immune system. Using Xcr1Cre-Gfp Rosa26LSL-DTA ApoE-/- mouse models, these data convincingly reveal an unexpected, non-redundant role of the XCL1-XCR1 axis in mediating cDC1 contributions to atherosclerosis.
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Reviewer #1 (Public review):
Summary:
In this study by Li et al., the authors re-investigated the role of cDC1 for atherosclerosis progression using the ApoE model. First, the authors confirmed the accumulation of cDC1 in atherosclerotic lesions in mice and humans. Then, in order to examine the functional relevance of this cell type, the authors developed a new mouse model to selectively target cDC1. Specifically, they inserted the Cre recombinase directly after the start codon of the endogenous XCR1 gene, thereby avoiding off-target activity. Following validation of this model, the authors crossed it with ApoE-deficient mice and found a striking reduction of aortic lesions (numbers and size) following a high-fat diet. The authors further characterized the impact of cDC1 depletion on lesional T cells and their activation state. Also, …
Reviewer #1 (Public review):
Summary:
In this study by Li et al., the authors re-investigated the role of cDC1 for atherosclerosis progression using the ApoE model. First, the authors confirmed the accumulation of cDC1 in atherosclerotic lesions in mice and humans. Then, in order to examine the functional relevance of this cell type, the authors developed a new mouse model to selectively target cDC1. Specifically, they inserted the Cre recombinase directly after the start codon of the endogenous XCR1 gene, thereby avoiding off-target activity. Following validation of this model, the authors crossed it with ApoE-deficient mice and found a striking reduction of aortic lesions (numbers and size) following a high-fat diet. The authors further characterized the impact of cDC1 depletion on lesional T cells and their activation state. Also, they provide in-depth transcriptomic analyses of lesional in comparison to splenic and nodal cDC1. These results imply cellular interactions between lesion T cells and cDC1. Finally, the authors show that the chemokine XCL1, which is produced by activated CD8 T cells (and NK cells), plays a key role in the interaction with XCR1-expressing cDC1 and particularly in the atherosclerotic disease progression.
Strengths:
The surprising results on XCL1 represent a very important gain in knowledge. The role of cDC1 is clarified with a new genetic mouse model.
Weaknesses:
My criticism is limited to the analysis of the scRNAseq data of the cDC1. I think it would be important to match these data with published data sets on cDC1. In particular, the data set by Sophie Janssen's group on splenic cDC1 might be helpful here (PMID: 37172103; https://www.single-cell.be/spleen_cDC_homeostatic_maturation/datasets/cdc1). It would be good to assign a cluster based on the categories used there (early/late, immature/mature, at least for splenic DC).
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Reviewer #2 (Public review):
This study investigates the role of cDC1 in atherosclerosis progression using Xcr1Cre-Gfp Rosa26LSL-DTA ApoE-/- mice. The authors demonstrate that selective depletion of cDC1 reduces atherosclerotic lesions in hyperlipidemic mice. While cDC1 depletion did not alter macrophage populations, it suppressed T cell activation (both CD4+ and CD8+ subsets) within aortic plaques. Further, targeting the chemokine Xcl1 (ligand of Xcr1) effectively inhibits atherosclerosis. The manuscript is well-written, and the data are clearly presented. However, several points require clarification:
(1) In Figure 1C (upper plot), it is not clear what the Xcr1 single-positive region in the aortic root represents, or whether this is caused by unspecific staining. So I wonder whether Xcr1 single-positive staining can reliably represent …
Reviewer #2 (Public review):
This study investigates the role of cDC1 in atherosclerosis progression using Xcr1Cre-Gfp Rosa26LSL-DTA ApoE-/- mice. The authors demonstrate that selective depletion of cDC1 reduces atherosclerotic lesions in hyperlipidemic mice. While cDC1 depletion did not alter macrophage populations, it suppressed T cell activation (both CD4+ and CD8+ subsets) within aortic plaques. Further, targeting the chemokine Xcl1 (ligand of Xcr1) effectively inhibits atherosclerosis. The manuscript is well-written, and the data are clearly presented. However, several points require clarification:
(1) In Figure 1C (upper plot), it is not clear what the Xcr1 single-positive region in the aortic root represents, or whether this is caused by unspecific staining. So I wonder whether Xcr1 single-positive staining can reliably represent cDC1. For accurate cDC1 gating in Figure 1E, Xcr1+CD11c+ co-staining should be used instead.
(2) Figure 4D suggests that cDC1 depletion does not affect CD4+/CD8+ T cells. However, only the proportion of these subsets within total T cells is shown. To fully interpret effects, the authors should provide:
a) Absolute numbers of total T cells in aortas.
b) Absolute counts of CD4+ and CD8+ T cells.(3) How does T cell activation mechanistically influence atherosclerosis progression? Why was CD69 selected as the sole activation marker? Were other markers (e.g., KLRG1, ICOS, CD44) examined to confirm activation status?
(4) Figure 7B: Beyond cDC1/2 proportions within cDCs, please report absolute counts of: Total cDCs,cDC1, and cDC2 subsets. Figure 7D: In addition to CD4+/CD8+ T cell proportions, the following should be included:
a) Total T cell numbers in aortas
b) Absolute counts of CD4+ and CD8+ T cells.(5) cDC1 depletion reduced CD69+CD4+ and CD69+CD8+ T cells, whereas Xcl1 depletion decreased Xcr1+ cDC1 cells without altering activated T cells. How do the authors explain these different results? This discrepancy needs explanation.
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