Proposed relevance of TLR-regulated actin changes to DC biology in vivo. DC migrate from peripheral tissues to lymph nodes under noninflammatory conditions using podosomes and their associated MMP activity as part of the migratory apparatus. Upon detection of a microbial stimulus, DC are proposed to enter a transient window of enhanced actin-driven antigen endocytosis, loss of podosomes, and appearance of prominent focal contacts, thus optimizing local antigen acquisition and suppressing migration. As endocytosis subsequently decreases, focal contacts are replaced by reappearing podosomes and migratory capacity is restored. Such DC conditioned by a microbial stimulus are potentially “immunizing” rather than “tolerizing.”