Abstract
Dendritic cells (DC) manipulate tissue homeostasis by recognizing dying cells and controlling immune functions. However, the precise mechanisms by which DC recognize different types of dying cells and devise distinct immunologic consequences remain largely obscure. Herein, we demonstrate that Milk-fat globule-EGF VIII (MFG-E8) is a critical mediator controlling DC immunogenicity in inflammatory microenvironments. MFG-E8 restrains DC-mediated uptake and recognition of necrotic cells. The MFG-E8-mediated suppression of necrotic cell uptake by DC resulted in the decreased proinflammatory cytokines production and activated signal components such as STAT3 and A20, which are critical to maintain tolerogenic properties of DC. Furthermore, the DC-derived MFG-E8 negatively regulates the cross-priming and effector functions of antigen-specific T cells upon recognition of necrotic cells. MFG-E8 deficiency enhances an ability of necrotic cell-primed DC to stimulate antitumor immune responses against established tumors. Our findings define what we believe to a novel mechanism whereby MFG-E8 regulates the immunogenicity of DC by modulating the modes of recognition of dying cells. Manipulating MFG-E8 levels in DC may serve as a useful strategy for controlling inflammatory microenvironments caused by various pathological conditions including cancer and autoimmunity.
Highlights
Dendritic cells (DC) serve as sentinels linking between innate and adaptive responses [1]
We demonstrate that MFG-E8-dependent recognition of apoptotic cells facilitates the tolerogenic activity of dendritic cells, whereas necrotic cell-mediated inflammation and cross-priming of antigenspecific cells is triggered by MFG-E8-deficient DC in a RIP1 (Receptor-interacting serine-threonine kinase)-dependent manner
The immature DC (iDC) treated with an inflammatory element such as CD40 ligand served as mature DC, in which MFG-E8 levels were low [9]
Summary
Dendritic cells (DC) serve as sentinels linking between innate and adaptive responses [1]. In addition to responses triggered via innate immune sensing such as pathogen- and/or endogenous danger-associated signals, the ability of DCs to activate adaptive immune responses relies mainly on the processing and presentation of immunogenic antigens [2,3]. This assumption implies that the mode of presentation and recognition of immunogenic antigens on DC may have a determinant role in the initiation and promotion of antigen-specific immune responses. We previously demonstrated that systemic targeting of MFG-E8 enhances antitumor immune responses by augmenting cross-presentation of immunogenic antigens [7,8,9]. We delineate the novel mechanisms by which DC regulate the delicate balance between immunity and tolerance by finetuning recognition of dying cells in an MFG-E8-dependent manner
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