Immunoreceptor tyrosine based inhibitory motif investing
Human cDCs, also called classical or myeloid dendritic cells, can be divided into at least two subsets. These results together with the recent observation showing that Dectinactivated pDCs promote Th2-type T cell responses while Dectinactivated cDCs do the opposite, point to the importance of combination of PAMP, PRR, and the cell context in the regulation of adaptive immune responses by innate immunity 4 , Negative Signaling by Itam-Associated Receptors in Macrophages Results obtained during the two last decennia show that immune receptors associated with an ITAM can generate stimulatory or, paradoxically, inhibitory signals 36 — 44 Figures 2 A,B.
These findings, obtained mostly in macrophages, provoked intense research into underlying mechanisms, as well as semantic debate The work of several laboratories suggests that positive or negative control of immune responses, in the case of ITAM alone, is determined by avidity of ITAM-associated receptors to their ligands. High- and low-avidity engagement of the immunoreceptor tyrosine-based activation motif ITAM -associated receptors in macrophages.
Tyrosine residues in ITAM motifs are shown by red circles. The importance of calcium signaling is highlighted by the finding that release of intracellular calcium activates the calcium-dependent phosphatase calcineurin, which is involved in the inhibition of TLR signaling by targeting the adaptor proteins MyD88 and TRIF A recent study showed that the TLR pathway in macrophages could be inhibited by another molecular mechanism, in which ITAM-associated low-avidity signaling inactivates MyD88 49 Figure 3.
Thus, the global activation status of the target cell will be responsible for the outcome of TLR signaling. The principal difference between pDCs and macrophages could reside in the localization and timing of the early steps of interaction of TLRs and ITAM-associated receptors. However, more recent studies have demonstrated a steady-state flow of TLR9 from endoplasmic reticulum to endolysosomes, where TLR9 is present in the mature, cathepsin-cleaved form 69 , 70 Figure 4 A.
Results from our laboratory have shown that 2 min after crosslinking of BDCA-2, SYK is phosphorylated, without assigning the phosphorylation to plasma membrane or endosome 73 Figure 4 B. Ubiquitination of these molecules depends on the cellular context. The capacity of pDCs to produce IFN-I and their central role at the interface of innate and adaptive immunity could make them important actors in antitumor immunity However, recent evidence suggests that tumor-associated TA pDCs recruited in breast and ovarian tumors are dysfunctional and their presence in these tumors is a negative prognostic factor for overall survival 82 — Recent data from the C.
Collectively, these results indicate that a tumor microenvironment induces a tolerogenic character in pDCs. The signal-switch hypothesis had a seminal role in the understanding of cross-regulation of cytokine- and TLR-signaling pathways in macrophages 8 , 9 , 28 , 39 , However, further studies showed that the ITAM-signaling pathway may be regulated in a special way in human pDCs 11 , 18 — Alternative pathway in cDCs 32 is shown by dotted arrow.
Under home-ostatic conditions in macrophages, the ITAM-associated receptors enable a fine-tuning of immune responses, including inhibition of IFN-I production and high sensitivity to extracellular cytokines. In an infection setting, ITAM-associated receptors in macrophages switch to signaling for robust production of cytokines including IFN-I, to cell activation and to low sensitivity to extracellular cytokines.
Differential effects of ITAM-mediated signaling in pDCs and macrophages would promote a coordinated cellular response to infection and inflammation. Interaction of the TLR pathway and ITAM signaling in pDCs plays an important role in control of the innate immune responses in viral infections 1 , 64 , 65 , cancer proliferation 20 , 83 , 84 , and autoimmune diseases 54 , Progress in understanding these interactions paves the way for the development of compounds to control activation of pDCs.
However, a growing body of evidence has emerged demonstrating that this is an oversimplification, and that ITIM-containing receptors are versatile regulators of platelet signal transduction, with functions beyond inhibiting ITAM-mediated platelet activation. Despite structural similarities and shared binding partners, including the Src homology 2 domain-containing protein-tyrosine phosphatases Shp1 and Shp2, knockout and transgenic mouse models have revealed distinct phenotypes and nonredundant functions for each ITIM-containing receptor in the context of platelet homeostasis.
These roles are likely influenced by receptor density, compartmentalization, and as-yet unknown binding partners. In this review, we discuss the diverse repertoire of ITIM-containing receptors in platelets, highlighting intriguing new functions, controversies, and future areas of investigation.
Introduction Platelets are small, anucleate fragments derived from megakaryocytes that are vital for maintaining hemostasis. A growing body of evidence has established that platelets also contribute to other pathophysiological processes, including atherogenesis, 1 inflammation, 2 wound repair, 3 angiogenesis, 4 blood-lymphatic vessel separation, 5 and cancer metastasis. Thus, understanding how platelets undergo this transition has broad implications for a number of diseases. Taking thrombosis and hemostasis as a paradigm of platelet activation, transition from the resting state relies on key receptors coming into contact with their cognate ligands in the vessel wall and transmitting activation signals within platelets.
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