LTβR and CD40: working together in dendritic cells to optimize immune responses

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.