Signaling by ITIM-Bearing Receptors

In order to respond adequately to pathogens without damaging the host, a balance between activating and inhibitory signals is required in the immune system. Over the past years a large number of inhibitory immune receptors has been identified. Most of these receptors contain one or several Immuno receptor Tyrosine-based Inhibitory Motif (ITIM)s in the intracellular part. These ITIMs recruit SH2 domaincontaining phosphatases, which can inhibit cellular activation. Studies using knock out mice have shown that ITIM-bearing receptors have crucial and non-redundant roles in the regulation of the immune system. However, the question remains why so many different ITIM-bearing receptors are required. ITIM-bearing receptors differ in their expression patterns and recognize different ligands, thus allowing for negative regulation at different levels and stages of an immune response. In addition, ITIM-bearing receptors may deliver different signals to the cell. Apart from the SH2 domain-containing phosphatases several ITIM-bearing receptors recruit other molecules that contribute to their function. In this review we will give an overview of the current model of ITIM-mediated signaling and discuss that alternative pathways may be used by ITIM-bearing receptors.