title: Unique ζ-chain motifs mediate a direct TCR-actin linkage critical for immunological synapse formation and T-cell activation.
abstract: TCR-mediated activation induces receptor microclusters that evolve to a defined immune synapse (IS). Many studies showed that actin polymerization and remodeling, which create a scaffold critical to IS formation and stabilization, are TCR mediated. However, the mechanisms controlling simultaneous TCR and actin dynamic rearrangement in the IS are yet not fully understood. Herein, we identify two novel TCR ζ-chain motifs, mediating the TCR's direct interaction with actin and inducing actin bundling. While T cells expressing the ζ-chain mutated in these motifs lack cytoskeleton (actin) associated (cska)-TCRs, they express normal levels of non-cska and surface TCRs as cells expressing wild-type ζ-chain. However, such mutant cells are unable to display activation-dependent TCR clustering, IS formation, expression of CD25/CD69 activation markers, or produce/secrete cytokine, effects also seen in the corresponding APCs. We are the first to show a direct TCR-actin linkage, providing the missing gap linking between TCR-mediated Ag recognition, specific cytoskeleton orientation toward the T-cell-APC interacting pole and long-lived IS maintenance.
authors.affiliation: The Lautenberg Center for General and Tumor Immunology, Hebrew University, Hadassah Medical School, Jerusalem, Israel.
authors.forename: Yair
authors.initials: Y
authors.lastname: Klieger
authors.forename: Osnat
authors.initials: O
authors.lastname: Almogi-Hazan
authors.forename: Eliran
authors.initials: E
authors.lastname: Ish-Shalom
authors.forename: Aviad
authors.initials: A
authors.lastname: Pato
authors.forename: Maor H
authors.initials: MH
authors.lastname: Pauker
authors.forename: Mira
authors.initials: M
authors.lastname: Barda-Saad
authors.forename: Lynn
authors.initials: L
authors.lastname: Wang
authors.forename: Michal
authors.initials: M
authors.lastname: Baniyash
mesh_terms: D000199:Actins / Q000378:metabolism; D020816:Amino Acid Motifs / Q000235:genetics; D000818:Animals; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D003599:Cytoskeleton / Q000378:metabolism*; D005260:Female; D054992:Immunological Synapses / Q000276:immunology / Q000378:metabolism*; D008213:Lymphocyte Activation / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D009154:Mutation / Q000235:genetics; D011940:Receptor Aggregation / Q000235:genetics; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000378:metabolism*; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: D000199:Actins; D016207:Cytokines; D011948:Receptors, Antigen, T-Cell; C054979:antigen T cell receptor, zeta chain
keywords: Actin microfilaments; Immunological synapse; T-cell activation; TCR