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

• Published in: Nature immunology Vol. 17; no. 5; pp. 574 - 582
• Main Authors: 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, Davis, Simon J
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.05.2016; Nature Publishing Group
• Subjects: 101/28; 13/106; 13/109; 13/95; 14; 14/35; 631/250/516; 631/45/535/1266; 82; 96; Biomedicine; Cell receptors; Cellular signal transduction; Crystallography, X-Ray; Genetic aspects; Health aspects; HEK293 Cells; Humans; Immune response; Immunology; Infectious Diseases; Jurkat Cells; Leukocyte Common Antigens - chemistry; Leukocyte Common Antigens - immunology; Leukocyte Common Antigens - metabolism; Lymphocyte Specific Protein Tyrosine Kinase p56(lck) - immunology; Lymphocyte Specific Protein Tyrosine Kinase p56(lck) - metabolism; Microscopy, Electron; Microscopy, Fluorescence - methods; Models, Molecular; Properties; Protein Structure, Tertiary; Receptors, Antigen, T-Cell - immunology; Receptors, Antigen, T-Cell - metabolism; Signal Transduction - immunology; T cells; T-Lymphocytes - immunology; T-Lymphocytes - metabolism; Time Factors; ZAP-70 Protein-Tyrosine Kinase - immunology; ZAP-70 Protein-Tyrosine Kinase - metabolism
• ISSN: 1529-2908; 1529-2916
• DOI: 10.1038/ni.3392

The receptor tyrosine phosphatase CD45 has an important role in T cell activation. Davis and colleagues resolve the structure of CD45 and provide molecular insights into how it contributes to productive T cell receptor triggering. 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.