ITIMs and ITAMs. The Yin and Yang of antigen and Fc receptor-linked signaling machinery

The initial stages of an immune response are regulated at the level of the cell-surface antigen and Fc receptors. The extracellular portions of these receptors provide immune specificity and determine the nature of the responding effector cells, whereas the intracellular portion transduces signals into the cell and determines the intensity and duration of the immune response. Recent studies led to the identification of two types of modules within the cytoplasmic region of receptor subunits that are critical for the activation and termination of signal transduction pathways. Phosphorylation of the conserved tyrosine residues within the two modules, the immunoreceptor tyrosine-based activation motif (ITAM) and the immunoreceptor tyrosine-based inhibition motif (ITIM), is followed by the recruitment of different sets of SH2-containing molecules to the receptor site. These proteins regulate the receptor-linked signal transduction pathways in a positive or a negative fashion, which is a reminiscent of the ancestral Yin-Yang principle.