Initiation of T cell signaling by CD45 segregation at 'close contacts'

Chang, Veronica T., Fernandes, Ricardo A., Ganzinger, Kristina A., Lee, Steven F., Siebold, Christian, McColl, James, Jönsson, Peter, Palayret, Matthieu, Harlos, Karl, Coles, Charlotte H., Jones, E. Yvonne, Lui, Yuan, Huang, Elizabeth, Gilbert, Robert J. C., Klenerman, David, Aricescu, A. Radu and Davis, Simon J. (2016) Initiation of T cell signaling by CD45 segregation at 'close contacts'. Nature Immunology, 17. 574–582. ISSN 1529-2908

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It has been proposed that the local segregation of kinases and the tyrosine phosphatase CD45 underpins T cell antigen receptor (TCR) triggering, but how such segregation occurs and whether it can initiate signaling is unclear. Using structural and biophysical analysis, we show that the extracellular region of CD45 is rigid and extends beyond the distance spanned by TCR-ligand complexes, implying that sites of TCR-ligand engagement would sterically exclude CD45. We also show that the formation of 'close contacts', new structures characterized by spontaneous CD45 and kinase segregation at the submicron-scale, initiates signaling even when TCR ligands are absent. Our work reveals the structural basis for, and the potent signaling effects of, local CD45 and kinase segregation. TCR ligands have the potential to heighten signaling simply by holding receptors in close contacts.

Item Type: Article
Faculty \ School: Faculty of Science
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Depositing User: LivePure Connector
Date Deposited: 15 Aug 2022 13:30
Last Modified: 22 Oct 2022 07:53
DOI: 10.1038/ni.3392

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