title: T cell receptor-proximal signals are sustained in peripheral microclusters and terminated in the central supramolecular activation cluster.
abstract: T cell receptor (TCR) signaling is initiated and sustained in microclusters; however, it's not known whether signaling also occurs in the TCR-rich central supramolecular activation cluster (cSMAC). We showed that the cSMAC formed by fusion of microclusters contained more CD45 than microclusters and is a site enriched in lysobisphosphatidic acid, a lipid involved in sorting ubiquitinated membrane proteins for degradation. Calcium signaling via TCR was blocked within 2 min by anti-MHCp treatment and 1 min by latrunculin-A treatment. TCR-MHCp interactions in the cSMAC survived these perturbations for 10 min and hence were not sufficient to sustain signaling. TCR microclusters were also resistant to disruption by anti-MHCp and latrunculin-A treatments. We propose that TCR signaling is sustained by stabilized microclusters and is terminated in the cSMAC, a structure from which TCR are sorted for degradation. Our studies reveal a role for F-actin in TCR signaling beyond microcluster formation.
authors.affiliation: Program in Molecular Pathogenesis, Skirball Institute of Biomolecular Medicine, Department of Pathology, New York University School of Medicine, 540 First Avenue, New York, New York 10016, USA.
authors.forename: Rajat
authors.initials: R
authors.lastname: Varma
authors.forename: Gabriele
authors.initials: G
authors.lastname: Campi
authors.forename: Tadashi
authors.initials: T
authors.lastname: Yokosuka
authors.forename: Takashi
authors.initials: T
authors.lastname: Saito
authors.forename: Michael L
authors.initials: ML
authors.lastname: Dustin
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D000906:Antibodies / Q000276:immunology; D002478:Cells, Cultured; D006649:Histocompatibility Antigens / Q000276:immunology; D017493:Leukocyte Common Antigens / Q000276:immunology; D050356:Lipid Metabolism; D008213:Lymphocyte Activation / Q000276:immunology*; D051379:Mice; D011485:Protein Binding; D011948:Receptors, Antigen, T-Cell / Q000276:immunology* / Q000378:metabolism*; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D051746:ZAP-70 Protein-Tyrosine Kinase / Q000378:metabolism
chemical_list: D000199:Actins; D000906:Antibodies; D006649:Histocompatibility Antigens; D011948:Receptors, Antigen, T-Cell; D051746:ZAP-70 Protein-Tyrosine Kinase; D017493:Leukocyte Common Antigens