Flt3 signaling-dependent dendritic cells protect against atherosclerosis

Early events in atherosclerosis occur in the aortic intima and involve monocytes that become macrophages. We looked for these cells in the steady state adult mouse aorta, and surprisingly, we found a dominance of dendritic cells (DCs) in the intima. In contrast to aortic adventitial macrophages, CD11c +MHC II hi DCs were poorly phagocytic but were immune stimulatory. DCs were of two types primarily: classical Flt3-Flt3L signaling-dependent, CD103 +CD11b - DCs and macrophage-colony stimulating factor (M-CSF)-dependent, CD14 +CD11b +DC-SIGN + monocyte-derived DCs. Both types expanded during atherosclerosis. By crossing Flt3 -/- to Ldlr -/- atherosclerosis-prone mice, we developed a selective and marked deficiency of classical CD103 + aortic DCs, and they were associated with exacerbated atherosclerosis without alterations in blood lipids. Concomitantly, the Flt3 -/-Ldlr -/- mice had fewer Foxp3 + Treg cells and increased inflammatory cytokine mRNAs in the aorta. Therefore, functional DCs are dominant in normal aortic intima and, in contrast to macrophages, CD103 + classical DCs are associated with atherosclerosis protection

Self-specific memory regulatory T cells protect embryos at implantation in mice

Regulatory T cells (Tregs) play crucial roles in both fetal and tumor development. We recently showed that immunosurveillance by pre-existing CD44CD62L activated/memory Tregs (amTregs) specific for self-Ags protects emergent tumor cells in mice. This Treg response of a memory type is more rapid than and dominates the antitumor response of tumor-specific effector T cells. In this study, we report striking similarities between the early Treg responses to embryo and tumor implantation. Tregs are rapidly recruited to uterus-draining lymph nodes and activated in the first days after embryo implantation in both syngeneic and allogeneic matings; express the markers of the amTreg subset; and are at least in part self-Ag specific, as seen in tumor emergence. Unlike in the tumor emergence setting, however, for which preimmunization against tumor Ags is sufficient for complete tumor eradication even in the presence of Tregs, Treg depletion is additionally required for high frequencies of fetus loss after preimmunization against paternal tissue Ags. Thus, amTregs play a major role in protecting embryos in both naive and preimmune settings. This role and the ensuing therapeutic potential are further highlighted by showing that Treg stimulation, directly by lowdose IL-2 or indirectly by Fms-related tyrosine kinase 3 ligand, led to normal pregnancy rates in a spontaneous abortion-prone model

Synthetic Melanin Acts as Efficient Peptide Carrier in Cancer Vaccine Strategy

We previously reported that a novel peptide vaccine platform, based on synthetic melanin nanoaggregates, triggers strong cytotoxic immune responses and significantly suppresses tumor growth in mice. However, the mechanisms underlying such an efficacy remained poorly described. Herein, we investigated the role of dendritic cells (DCs) in presenting the antigen embedded in the vaccine formulation, as well as the potential stimulatory effect of melanin upon these cells, in vitro by coculture experiments and ELISA/flow cytometry analysis. The vaccine efficiency was evaluated in FLT3-L−/− mice constitutively deficient in DC1, DC2, and pDCs, in Zbtb46DTR chimera mice deficient in DC1 and DC2, and in LangerinDTR mice deficient in dermal DC1 and Langerhans cells. We concluded that DCs, and especially migratory conventional type 1 dendritic cells, seem crucial for mounting the immune response after melanin-based vaccination. We also assessed the protective effect of L-DOPA melanin on peptides from enzymatic digestion, as well as the biodistribution of melanin–peptide nanoaggregates, after subcutaneous injection using [18F]MEL050 PET imaging in mice. L-DOPA melanin proved to act as an efficient carrier for peptides by fully protecting them from enzymatic degradation. L-DOPA melanin did not display any direct stimulatory effects on dendritic cells in vitro. Using PET imaging, we detected melanin–peptide nanoaggregates up to three weeks after subcutaneous injections within the secondary lymphoid tissues, which could explain the sustained immune response observed (up to 4 months) with this vaccine technology

M‐CSF‐mediated macrophage development is dominantly inhibited by NOD2 signaling for replenishment of immunogenic dendritic cells

International audienceDespite recent advances, it remains unclear whether monocyte‐derived dendritic cells (moDCs) represent alternative context‐dependent fate in the gut. We found here that Nod2‐ dependent sensing of bacteria lowers the ability of circulating monocytes to respond to M‐CSF for generating moDCs. Such inhibitory effect on monocyte‐to‐macrophage transition was prevented upon blockade of TNF‐α. Recognition of the gut microbiota by Nod2 was sufficient to promote the expansion of moDCs within the colonic mucosa. A competitive bone marrow transplant model further demonstrated that Nod2 promotes the conversion of monocytes into dendritic cells. Equally of importance, tumours with the highest transcript levels of NOD2 were associated with a favorable prognosis and characterized by an enrichment of a gene signature related to moDCs. This study implicates that Nod2‐dependent sensing of the gut microbiota influences monocytic lineage commitment into dendritic cells, which sets the stage for future investigations to achieve accurate outcome prediction in colorectal cancer

The receptor tyrosine kinase FIt3 is required for dendritic cell development in peripheral lymphoid tissues

Dendritic cell (DC) development begins in the bone marrow but is not completed until after immature progenitors reach their sites of residence in lymphoid organs. The hematopoietic growth factors regulating these processes are poorly understood. Here we examine the effects of FMS-like tyrosine kinase 3 (Flt3) signaling on macrophage DC progenitors (MDP) in the bone marrow and on peripheral DCs. We find that the MDP compartment is responsive to super–physiologic levels of Flt3 ligand (Flt3L) but is not dependent on Flt3 for its homeostatic maintenance in vivo. In contrast, Flt3 is essential in regulation of homeostatic DC development in the spleen where it is required to maintain normal numbers of DCs by controlling their division in the periphery