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Treg-mediated suppression of atherosclerosis requires MYD88 signaling in DCs
Manikandan Subramanian, … , Goran K. Hansson, Ira Tabas
Manikandan Subramanian, … , Goran K. Hansson, Ira Tabas
Published December 21, 2012
Citation Information: J Clin Invest. 2013;123(1):179-188. https://doi.org/10.1172/JCI64617.
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Research Article Cardiology Article has an altmetric score of 12

Treg-mediated suppression of atherosclerosis requires MYD88 signaling in DCs

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Abstract

TLR activation on CD11c+ DCs triggers DC maturation, which is critical for T cell activation. Given the expansion of CD11c+ DCs during the progression of atherosclerosis and the key role of T cell activation in atherogenesis, we sought to understand the role of TLR signaling in CD11c+ DCs in atherosclerosis. To this end, we used a mouse model in which a key TLR adaptor involved in DC maturation, MYD88, is deleted in CD11c+ DCs. We transplanted bone marrow containing Myd88-deficient CD11c+ DCs into Western diet–fed LDL receptor knockout mice and found that the transplanted mice had decreased activation of effector T cells in the periphery as well as decreased infiltration of both effector T cells and Tregs in atherosclerotic lesions. Surprisingly, the net effect was an increase in atherosclerotic lesion size due to an increase in the content of myeloid-derived inflammatory cells. The mechanism involves increased lesional monocyte recruitment associated with loss of Treg-mediated suppression of MCP-1. Thus, the dominant effect of MYD88 signaling in CD11c+ DCs in the setting of atherosclerosis is to promote the development of atheroprotective Tregs. In the absence of MYD88 signaling in CD11c+ DCs, the loss of this protective Treg response trumps the loss of proatherogenic T effector cell activation.

Authors

Manikandan Subramanian, Edward Thorp, Goran K. Hansson, Ira Tabas

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Figure 7

Schematic showing the mechanism of atheroprotective action of Tregs.

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Schematic showing the mechanism of atheroprotective action of Tregs.
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In atherosclerosis, mature DCs activate both Teff cells and Tregs. This study suggests that the atheroprotective effect of Tregs dominates. Tregs exert their atheroprotective action via suppression of Teff cells and inflammatory macrophages (Mϕs), and they suppress monocyte recruitment by decreasing MCP-1 production in a TGF-β–dependent manner.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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