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MHC class II-restricted antigen presentation by plasmacytoid dendritic cells drive pro-atherogenic immunity

      Plasmacytoid dendritic cells (pDCs) bridge innate and adaptive immune responses and are important regulators of immuno-inflammatory diseases. However, their role in atherosclerosis remains elusive. Antibody–mediated depletion of pDCs significantly alters atherosclerosis in mice but results and reported mechanisms have differed between studies. Here, we used genetic approaches to investigate the role of pDCs in atherosclerosis. Partial but selective pDC deficiency was achieved using CD11c-Cre x Tcf4–/flox bone marrow transplanted into Ldlr–/– mice. Compared to control Ldlr–/– chimeric mice, CD11c-Cre x Tcf4–/flox mice had reduced atherosclerosis levels. This was associated with significantly reduced numbers of tissue pDCs and occurred despite enhanced numbers of CD11chi/MHCIIhi conventional DCs. To begin to understand the mechanisms by which pDCs regulate atherosclerosis, we studied chimeric Ldlr–/– mice with selective MHCII deficiency on pDCs. Significantly, these mice also developed reduced atherosclerosis compared to controls without reductions in pDC numbers or changes in conventional DCs. MHCII-deficient pDCs showed defective stimulation of both ApoB100-specific CD4+ T cells in response to native LDL, and OT-II T cells in response to ovalbumin. IN contrast, IFN-α production was not affected. This study supports a pro-atherogenic role for pDCs in murine atherosclerosis and identifies a previously unsuspected critical role for MHCII-restricted antigen presentation by pDCs in driving pro-atherogenic T cell immunity.
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