Both activating and inhibitory FcαR signaling require the FcRγ-ITAM 68. In addition, inhibitory effects on TLR signaling have been recently shown for various other ITAM-coupled receptors 69–71, as will be discussed later (see ITAM signaling may negatively regulate TLR response). The inhibitory effect of monomeric FcαR learn more ligation may be an important mechanism to set an immune activation threshold under physiological serum conditions. As discussed, intracellular signaling

by various receptors, such as TLRs, chemokine GPCRs, and Fc receptors can be modulated by inhibitory receptors. Are inhibitory receptors limited in the range of activation signals they can regulate? The inhibitory signaling of ITIM-bearing receptors is classically studied in the context of activation signals relayed by immunoreceptor tyrosine-based activating motifs (ITAMs), which are phosphorylated by SFK upon receptor ligation 72. SFKs are also implicated in the signaling of other activating Proteasome activity receptors, such as TLR signaling 73, cytokine and growth factor receptors, and integrin signaling 74. It has been postulated that phosphorylation of ITIMs by SFK is dependent on in trans coengagement of inhibitory and activating receptors. Alternatively, clustering of inhibitory receptors may be sufficient to recruit SFK that phosphorylates the ITIMs 72. In the latter case, activation of ITIM-bearing receptors would not involve clustering

with Amino acid an activating receptor, and would be independent of SFK recruited by the activating receptor, thus broadening the quantity of activating signals that can be inhibited. The role of PIR-B in chemotaxis is supportive of SFK-independent recruitment by inhibitory receptors. Neutrophils deficient in the granulocyte SFK members Hck and Fgr migrate normally

through transwell filters and even show enhanced migration in response to chemoattractants 22, indicating that chemokine-induced migration does not require SFK. Nevertheless, PIR-B can negatively regulate chemokine signaling since PIR-B-deficient neutrophils show increased migration in response to chemoattractants 22. The fact that PIR-B phosphorylation is impaired in Hck- and Fgr-deficient cells 22 suggests that PIR-B is phosphorylated by SFK. Thus, enhanced migration in Hck- and Fgr-deficient cells may be due to the lack of signaling by PIR-B and possibly other inhibitory receptors. This illustrates that the inhibitory capacity of ITIM-bearing receptors is not dependent on SFK recruited by activating receptors and broadens the range of activating signals that are possibly modulated. As already discussed (see What effector molecules mediate inhibition?), inhibitory receptors may recruit alternative molecules to modulate activation pathways. Nevertheless, SHP-1 and SHP-2 are generally engaged by ITIM-bearing receptors, and their inhibitory capacity is often impaired in SHP-1/2-deficient cells 75–77.