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Given pathogen diversity, including modes of entry, replication cycles, and strategies of immune evasion and spread, all successive waves of the immune response ought to be tailored to the specific immune threat, leading us to postulate that immune sentinel functions by macrophages and dendritic cells ought to be highly stimulus-specific. Here we review the experimental evidence for stimulus-specific responses by immune sentinel cells which initiate and coordinate immune responses, as well as the mechanisms by which this specificity may