The balance between activating and inhibitory signals is essential to control immune responses to microorganisms. Innate and adaptive immune responses are regulated by receptors that signal through either an immunoreceptor tyrosine-based activation motif (ITAM) or an immunoreceptor tyrosine-based inhibitory motif (ITIM). When clustered, these motifs are, respectively, responsible for activating and inhibitory signals. Recently, the concept of inhibitory ITAM (ITAM i) has emerged as a new means to negatively control the immune response. In this Opinion, we will discuss the ability of Escherichia coli to evade the immune system by eliciting ITAM i function through FcγRIII (CD16) on phagocytes leading to uncontrolled systemic infection and sepsis. Elucidating such mechanisms will open opportunities for specific therapeutic manipulation of ITAM i-based signaling pathways.