Expansion Of CD11c Research Articles

Dendritic Cells and Microglia Have Non-redundant Functions in the Inflamed Brain with Protective Effects of Type 1 cDCs

SummaryBrain CD11c+ cells share features with microglia and dendritic cells (DCs). Sterile inflammation increases brain CD11c+ cells, but their phenotype, origin, and functions remain largely unknown. We report that, after cerebral ischemia, microglia attract DCs to the inflamed brain, and astroglia produce Flt3 ligand, supporting development and expansion of CD11c+ cells. CD11c+ cells in the inflamed brain are a complex population derived from proliferating microglia and infiltrating DCs, including a major subset of OX40L+ conventional cDC2, and also cDC1, plasmacytoid, and monocyte-derived DCs. Despite sharing certain morphological features and markers, CD11c+ microglia and DCs display differential expression of pattern recognition receptors and chemokine receptors. DCs excel CD11c− and CD11c+ microglia in the capacity to present antigen through MHCI and MHCII. Of note, cDC1s protect from brain injury after ischemia. We thus reveal aspects of the dynamics and functions of brain DCs in the regulation of inflammation and immunity.

Dendritic Cells and Microglia Have Non-Redundant Functions in the Inflamed Brain with Protective Effects of Type 1 cDCs

Brain CD11c+ cells share features with microglia and dendritic cells (DCs). Sterile inflammation increases brain CD11c+ cells but their phenotype, origin, and functions remain largely unknown. We report that after cerebral ischemia, microglia attract DCs to the inflamed brain and astroglia produce Flt3 ligand supporting development and expansion of CD11c+ cells. CD11c+ cells in the inflamed brain are a complex population derived from proliferating microglia and infiltrating DCs, including a major subset of OX40L+ conventional cDC2, and also cDC1, plasmacytoid and monocyte-derived DCs. Despite sharing certain morphological features and markers, CD11c+ microglia and DCs display differential expression of pattern recognition receptors and chemokine receptors. DCs excel CD11c- and CD11c+ microglia in the capacity to present antigen through MHC I and MHC II. Of note, cDC1s protect from brain injury after ischemia. We thus reveal novel aspects of the dynamics and functions of brain DCs in regulation of inflammation and immunity.

Abstract 5139: Adjuvant immunotherapy targeting CSF1R to limit metastatic progression

Abstract Metastasis is often considered a late stage event, although the first changes in the metastatic site occur very early during localized primary tumor development. Although understanding of these initiating events is limited, immune suppression plays an essential role in allowing for the outgrowth of disseminating tumor cells. Targeting this immune suppressive milieu can hold promise to effectively inhibit metastatic progression. Colony stimulating factor-one (CSF-1) is overexpressed by many diverse tumor types and can induce expansion and recruitment of CSF-1 receptor (CSF-1R) expressing cells. CSF-1R is expressed on a multitude of myeloid cells including inflammatory monocytes, myeloid derived suppressor cells and macrophages, which are key immune suppressive cells in a primary tumor site. Using a metastatic rhabdomyosarcoma model, we have identified expansion of immune suppressive myeloid cells in the early metastatic microenvironment. PLX3397, which is small molecular inhibitor that selectively targets CSF-1R, Kit and Oncogenic FLT3, was used to determine the impact of targeting this immune suppressive microenvironment in limiting metastatic progression. PLX3397 and GW2580, a selective CSF1R inhibitor, reduce the immune suppressive capacity of bone marrow-derived monocytes on activated T cells. Adjuvant therapy with PLX3397 in resected rhabdomyosarcoma reduces metastatic spread. Targeting CSF-1R is associated with an expansion of CD11C expressing antigen presenting cells in the metastatic tissue and in combination with PD-1 blockade improves anti-tumor immunity. Continued investigation of combination immunotherapy with metastatic microenvironment targeting in the adjuvant setting holds promise to limit metastatic spread. Citation Format: Justin Evans, Amber J. Giles, Meera Murgai, Miki Kasai, Caitlin Reid, Rosandra Natasha Kaplan. Adjuvant immunotherapy targeting CSF1R to limit metastatic progression. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 5139.

Treg-mediated suppression of atherosclerosis requires MYD88 signaling in DCs

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.

IL‐33 promotes DC development in BM culture by triggering GM‐CSF production

Short-term DC cultures generated with GM-CSF and other cytokines have markedly improved our ability to study the immunobiology of DC. Here, we tested 65 cytokines individually for their potential to promote the generation of CD11c+ cells in a murine BM culture system. In addition to several cytokines known to promote DC survival and/or growth, IL-33 was found to augment DC development time- and dose-dependently. Although the resulting CD11c+ cells generated in the presence of IL-33 exhibited a typical dendritic morphology, they expressed MHC class II molecules only at modest levels, showed negligible responses to TLR ligands, produced no detectable IL-12 p70, displayed PD-L1 and PD-L2 on the surface, and failed to activate immunologically naïve T cells efficiently. IL-33-induced expansion of CD11c+ cells was completely blocked by anti-GM-CSF mAb, and GM-CSF mRNA and protein expression in BM culture was markedly elevated by added IL-33, indicating that IL-33 promotes in vitro DC generation indirectly by a GM-CSF-dependent manner. With regard to the cellular source, IL-33-dependent GM-CSF production was observed exclusively within the CD45+/FcepsilonRI+ BM population. Not only do our results reinforce the notion that GM-CSF serves as a primary DC growth factor, but they also reveal a previously unrecognized mechanism supporting DC development.

GM-CSF expanded tolerogenic CD11c+CD8a− dendritic cells can induce autoantigen specific CD4+ CD25+ Foxp3+ T regulatory cells (128.11)

Abstract Treatment of CBA/j mice with Granulocyte Macrophage Colony Stimulating Factor (GM-CSF), a potent growth factor for dendritic cells can prevent and suppress ongoing experimental autoimmune thyroiditis (EAT). GM-CSF treatment causes expansion of CD11c+CD8a− myeloid dendritic cells (DCs) with a consequent increase in CD4+CD25+ T regulatory cells (Tregs) in an EAT model. In this study, we investigated the significance of the expansion of CD8a− myeloid DCs by GM-CSF and its direct role in inducing CD4+CD25+Foxp3+ T regs. Co-culture of CD4+ T cells with CD8a-ve DCs from GM-CSF treated mice in the presence of mouse thyroglobulin (mTg) induced an increase in the number of CD4+CD25+Foxp3+ T cells. These Foxp3+ T cells produced high levels of IL-10. These T regs could suppress the mTg specific proliferation of effector CD4+CD25− T cells, which was reversed upon addition of anti-IL10R antibodies. In contrast, GM-CSF treated CD8a+ lymphoid DCs failed to show a significant suppression of mTg specific T cell proliferation. In vivo experiments in a SCID mouse model revealed that GM-CSF treated SCID mice could induce increased numbers of Foxp3 and IL-10 expressing CD4+ T cells that were adoptively transferred from wild type CBA/j mice. These results indicate that GM-CSF acts directly on CD8a− myeloid DCs in the absence of T cells and renders them tolerogenic in that they cause expansion of CD4+Foxp3+ Tregs, which suppress mTg specific proliferation in an IL-10 dependent manner. NIH 1RO1AI058190