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Thank you for visiting nature. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser or turn off compatibility mode in Internet Explorer. In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript. The negative regulation of lymphocyte activation has become an area of intense investigation and excitement. In particular, the use of monoclonal antibodies that block inhibitory receptors expressed by T cells — the so-called checkpoint inhibitors — has shown unprecedented clinical benefits in patients with many different types of cancer.

But at the start of the s, the concept that the engagement of cell surface receptors with their cognate ligands might inhibit immune cell activation was only beginning to be unveiled. In those days, the dissection of the signalling pathways that mediate T cell activation was an extremely hot topic. In his seminal scientific correspondence to Nature , 'Antigen receptor tail clue', Michael Reth identified ITAMs immunoreceptor tyrosine-based activation motifs in the intracellular domains of the CD3 subunits that associate with the T cell receptor TCR.

My excitement at these developments was piqued by the discovery of signals that could block the activation of another group of lymphocytes, the natural killer NK cells, which prompted the dissection of the signalling pathways involved in this negative regulation.

The authors coined the term ITIM immunoreceptor tyrosine-based inhibition motif to describe this inhibitory intracellular signalling domain. For me, this paper was episode 1 of a vast saga in which several of us identified a large family of ITIM-bearing receptors and showed that their mode of action was through the recruitment of protein tyrosine phosphatases, such as SHP1, or lipid phosphatases, such as SHIP1.

Today, there is still considerable effort being made to understand the negative regulation of immune cell activation as well as the dynamic equilibrium between activating and inhibitory receptors that controls immune cell behaviour. Immunity 3 , — Article Google Scholar. Download references. You can also search for this author in PubMed Google Scholar. Correspondence to Eric Vivier. Reprints and Permissions. Vivier, E. ITIMs: episode 1 of the inhibitory saga.

Nat Rev Immunol 18, 4 Download citation. Published : 27 November Issue Date : January Anyone you share the following link with will be able to read this content:. Sorry, a shareable link is not currently available for this article. Provided by the Springer Nature SharedIt content-sharing initiative.

Advanced search. Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily. Skip to main content Thank you for visiting nature. Download PDF. Subjects Signal transduction.

The author is co-founder and shareholder of Innate Pharma. Immunity 3 , — Article Google Scholar Download references. Rights and permissions Reprints and Permissions. About this article. Cite this article Vivier, E. Copy to clipboard. Search Search articles by subject, keyword or author. Show results from All journals This journal.

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