Ly49Q binds MHCI and is functionally Talazoparib concentration analogous to human killer Ig-like receptors (KIRs) 83. Intriguingly, it was recently demonstrated that in addition to binding HLA, KIR3DL2 can directly bind CpG DNA, which leads to enhanced cytokine production 84. It would be interesting to examine whether Ly49Q has similar binding capacities. The importance of cellular localization of inhibitory receptors is also evident from the studies in NK cells. Inhibitory receptor-mediated inhibition of NK-cell activity is known to act locally, as NK cells
contacting both resistant and susceptible target cells are capable of selective killing of susceptible target cells 85, 86. Inhibitory receptors present in the immunological synapse between RGFP966 cost target cell and effector cell mediate the localized inhibition of activating receptor cytotoxicity 85. Thus, SHP-1 and SHP-2 play an important role in ITIM-mediated inhibition of various activation pathways (Fig. 2). As described by the study of Kong 14 and Sasawatari et al. 23,
the mode of action of SHP-1 and SHP-2 may involve the mechanisms other than dephosphorylation of upstream molecules; controlled cellular localization of the receptor itself or associated molecules may lead to inhibition of cell activation by sequestration or, conversely, be essential in cellular activity. Possibly, the capacity to colocalize with activating receptors may determine whether the inhibitory receptor is selective in its action or has broad capacity. Thymidylate synthase Few
groups have thoroughly addressed this issue; expansion of these studies would further improve our understanding on the mechanism behind inhibitory receptor function. In addition to ITIM-mediated inhibition of TLR responses, ITAM-mediated signaling may also inhibit TLR signaling. For example, DAP12-deficient macrophages show increased cytokine production after stimulation with TLR ligands such as LPS and CpG 70. As with the FcαR, it has been hypothesized that clustering of DAP12 by high-avidity interactions will result in activating effects, whereas DAP12 recruitment following low-avidity interactions will lead to inhibitory effects 87. Low-avidity receptor ligation would result in a weak phosphorylation of the ITAMs and basal Syk phosphorylation, which leads to inhibition of TLR signaling. The nature of the DAP12 recruiting receptor may determine whether TLR signaling is impaired. Supportive of this concept is that TREM-2-DAP12 chimeras lead to inhibitory effects on TLR signaling, whereas TREM-1 chimeras do not 71. Also integrin signaling may reduce TLR activation. DAP12 and FcRγ are required to relay integrin signals in neutrophils and macrophages, thus coupling integrin ligation to Syk activation and downstream signaling events 69, 88.