Mature dendritic cells (DCs) are crucial for the induction of adaptive immune responses and perturbed DC homeostasis can result in autoimmune disease. Either uncontrolled expansion or enhanced survival of DCs can result in a variety of autoimmune diseases in mouse models. In addition, increased maturation signals, through overexpression of surface Toll-like receptors (TLRs) or stimulation by type I interferon (IFN), has been associated with systemic autoimmunity. Whereas recent studies have focused on identifying factors required for initiating the maturation process, the possibility that resting DCs also express molecules that 'hold' them in an immature state has generally not been considered. Here we show that nuclear factor-κB1 (NF-κB1) is crucial for maintaining the resting state of DCs. Self-antigen-pulsed unstimulated DCs that do not express NF-κB1 were able to activate CD8(+) T lymphocytes and induce autoimmunity. We further show that NF-κB1 negatively regulates the spontaneous production of tumor necrosis factor-α (TNF-α), which is associated with increased granzyme B expression in cytotoxic T lymphocytes (CTLs). These findings provide a new perspective on functional DC maturation and a potential mechanism that may account for pathologic T cell activation.
Members of the tumour necrosis factor (TNF) superfamily have been implicated in a wide range of biological functions, and their expression by cells of the immune system makes them appealing targets for immunomodulation. One common theme for TNF superfamily members is their coordinated expression at the interface between antigen-specific T cells and antigen-presenting dendritic cells and, by virtue of this expression pattern, TNF superfamily members can shape T cell immune responses. Understanding how to manipulate such functions of the TNF superfamily may allow us to tip the balance between immunity and tolerance in the context of human disease.
Generating an immune response tailored to destroy an infecting organism while limiting bystander damage involves guiding T-cell activation using a variety of cues taken from the immunogen (antigen type, dose, and persistence, accompanying danger signals) as well as the host (tissue environment, T-cell frequency, and affinity for antigen). Dendritic cells (DCs) serve as translators of much of this information and are critically required for effective pathogen and tumor clearance. Moreover, dysregulation of DC activation can lead to autoimmunity. Inhibition of the lymphotoxin (LT) and CD40 pathways has been shown to be effective at quieting inflammation in settings where DC-T-cell interactions are key instigators of disease progression. In this review, we compare and contrast the CD40 and LT pathways in the context of receptor/ligand expression, signal transduction, and DC biology. We provide evidence that these two pathways play complementary roles in DC cytokine secretion, thus indirectly shaping the nature of the CD8(+) T-cell response to foreign antigen. Given the distinct role of these pathways in the context of DC function, we propose that dual therapies targeted at both the CD40 and LTβ receptor may have therapeutic potential in silencing DC-driven autoimmunity or in promoting tumor clearance.
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