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ISSN 在线: 2162-6472

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DOI: 10.1615/CritRevImmunol.v20.i2.10
14 pages

Immunoreceptor Tyrosine-Based Inhibitory Motifs on Activating Molecules

Nicholas R. StC. Sinclair
Department of Microbiology and Immunology, The University of Western Ontario, London, Ontario, Canada, N6A 5C1

ABSTRACT

Immunoreceptor tyrosine-based inhibitory motifs (ITIMs) have the restricted consensus sequence V/I/xYxxL/V, but may be more broadly defined by the sequence V/I/L/SxYxxL/V/I/S. If one includes the ITIM of CTLA-4, then the sequence becomes ΨxYxxΨ, where >Ψ represents amino acids with nonpolar side chains. Aside from their presence in various inhibitory molecules, ITIMs are also found on many activating receptors and pathways. ITIMs with the restricted consensus sequence occur on IL-4Rα, IL-3Rβ type II, gpl30 cytokineR, OB-R (leptinR), LIF-Rβ TNF-RI, G-CSF-R, PDGF-R, Blk, Ctk/Ntk, Lsk, Zap-70, PKB/RACα, PKC-α, PKC-β, PKC-γ, PKC-δ, PKC-ζ, PKC-ε, PKC-η, PKC-Φ, PKC-μ, calmodulin-dependent kinase IIδ, SLP-76-associated protein, FYN-binding protein, She binding protein, RasGRF2, CDC25 homologue, Jak2, Jak3, PLCβ1, and PLCβ3. If ITIMs are defined by a broader consensus sequence, the list of ITIMs on activating molecules becomes even larger. In some instances, these ITIMs have been shown to associate with inhibitory phosphatases. Whether these ITIMs on activating receptors/pathways are necessary and sufficient for negative control of activating events and for immunologic tolerance is not yet known. In some instances, ITIMs on coinhibitory receptors are also required for appropriate negative regulation. By studying events leading to negative control during activation and to immunologic tolerance, it should be possible to discern the balance between antigen receptor-based negative events and coinhibition.


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