The conundrum of inhibitory signaling by ITAM‐containing immunoreceptors: Potential molecular mechanisms

Immunoreceptor signals must be appropriately transduced and regulated to achieve effective immunity while controlling inflammation and autoimmunity. It is generally held that these processes are mediated by the interplay of distinct activating and inhibitory receptors via conserved activating (ITAM) and inhibitory (ITIM) signaling motifs. However, recent evidence indicates that under certain conditions incomplete phosphorylation of ITAM tyrosines leads to inhibitory signaling. This new regulatory function of ITAMs has been termed ITAMi (inhibitory ITAM). Here we discuss the potential molecular mechanisms of inhibitory signaling by ITAM-containing receptors.