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A requirement for two independent signals helps to ensure that T\u2010cell responses are initiated only in response to <jats:italic>bona fide<\/jats:italic> infectious threats. Our studies have led us to conclude that initiation of innate immune responses to pathogens also often requires two signals: signal one is initiated by a microbe\u2010derived ligand, such as lipopolysaccharide (LPS) or flagellin, whereas signal two conveys additional contextual information that often accompanies infectious microbes. Although signal one alone is sufficient to initiate many innate responses, certain responses\u2014particularly ones with the potential for self\u2010damage\u2014require two signals for activation. Many of our studies have employed the intracellular bacterial pathogen <jats:italic>Legionella pneumophila<\/jats:italic>, which has been established as a valuable model for understanding innate immune responses. 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