MHC Class II–Restricted Antigen Presentation by Plasmacytoid Dendritic Cells Drives Proatherogenic T Cell Immunity

Abstract

Background-Plasmacytoid dendritic cells (pDCs) bridge innate and adaptive immune responses and are importantregulators of immuno-inflammatory diseases. However, their role in atherosclerosis remains elusive. Methods and Results-Here, we used genetic approaches to investigate the role of pDCs in atherosclerosis. Selective pDC deficiency in vivo was achieved using CD11c-Cre × Tcf4 -/flox bone marrow transplanted into Ldlr -/-mice. Compared with control Ldlr -/-chimeric mice, CD11c-Cre × Tcf4 -/flox mice had reduced atherosclerosis levels. 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 with controls without reductions in pDC numbers or changes in conventional DCs. MHCII-deficient pDCs showed defective stimulation of apolipoprotein B100-specific CD4 + T cells in response to native low-density lipoprotein, whereas production of interferon-α was not affected. Finally, the atheroprotective effect of selective MHCII deficiency in pDCs was associated with significant reductions of proatherogenic T cell-derived interferon-γ and lesional T cell infiltration, and was abrogated in CD4 + T cell-depleted animals. Conclusions-This

Plasmacytoid Dendritic Cells in Atherosclerosis

“…7 However, recent efforts to address the role of pDCs in atherogenesis by antibody-aided depletion were rather inconsistent and left unsettled whether pDCs are detrimental or beneficial in their pathophysiology. [8][9][10] In this issue of Circulation, Sage et al 11 provide new evidence that pDCs act proatherogenic in murine atherosclerosis by presenting (plaque derived) antigens via major histocompatibility complex (MHC) II and inducing CD4 + T-cell immunity. The authors circumvent the potential pitfalls of antibody depletion, deploying 2 elegant genetic loss-of-function models to interrogate the involvement of pDCs in atherosclerosis.…”

“…Moreover, (target cell-bound) depletion antibodies could well exert different patterns of Fcγ receptor activation than the isotype control, potentially leading to disparate leukocyte activation, whereas acute massive cell death has been seen to elicit immunosuppressive or stimulatory effects, depending on its context. The aforementioned limitations underpin the importance of more refined genetic approaches, such as the CD11c-Cre×Tcf4 -/flox and the μMT:pIII+IV -/-models, deployed by Sage et al, 11 to firmly establish the role of DC subsets, such as pDCs in the pathophysiology of atherosclerosis.…”

“…It is unclear whether this reflects differences in pDC versus cDC colocalization with T cells in plaque or plaque-draining lymph nodes 17 or in their trafficking routes to peripheral (inflamed) lymphoid organs. Nevertheless, the data presented in the study of Sage et al 11 hints toward more efficient uptake and presentation of plaque neoepitopes by pDCs than cDCs, a conception with major implications for future plaque-targeting immunization and vaccination strategies. 18 In conclusion, the current study by Sage et al 11 and previously published reports on pDC depletion illustrate their pleiotropism in the complex pathophysiology of atherosclerosis.…”

“…Nevertheless, the data presented in the study of Sage et al 11 hints toward more efficient uptake and presentation of plaque neoepitopes by pDCs than cDCs, a conception with major implications for future plaque-targeting immunization and vaccination strategies. 18 In conclusion, the current study by Sage et al 11 and previously published reports on pDC depletion illustrate their pleiotropism in the complex pathophysiology of atherosclerosis. Local and peripheral factors are critical in regulating the pDC phenotype to favor immune activation or tolerance.…”

“…On the other hand, we cannot at this point exclude that pDC will act immunosuppressive during stages of low-grade inflammation. 19 The use of a reproducible and precise animal model is vital in this context, as highlighted by the study of Sage et al 11 Their findings, although clearly adding to our understanding of pDC functionality in atherogenesis, also identify pDC-based immunotherapy as an attractive new target for treating atherosclerosis. PDCs could be instructed to mediate tolerance toward plaque neoepitopes, as shown for solid organs and hematopoietic stem cell transplantation.…”