title: Actin foci facilitate activation of the phospholipase C-γ in primary T lymphocytes via the WASP pathway.
abstract: Wiscott Aldrich Syndrome protein (WASP) deficiency results in defects in calcium ion signaling, cytoskeletal regulation, gene transcription and overall T cell activation. The activation of WASP constitutes a key pathway for actin filament nucleation. Yet, when WASP function is eliminated there is negligible effect on actin polymerization at the immunological synapse, leading to gaps in our understanding of the events connecting WASP and calcium ion signaling. Here, we identify a fraction of total synaptic F-actin selectively generated by WASP in the form of distinct F-actin 'foci'. These foci are polymerized de novo as a result of the T cell receptor (TCR) proximal tyrosine kinase cascade, and facilitate distal signaling events including PLCγ1 activation and subsequent cytoplasmic calcium ion elevation. We conclude that WASP generates a dynamic F-actin architecture in the context of the immunological synapse, which then amplifies the downstream signals required for an optimal immune response.
authors.affiliation: Skirball Institute of Biomolecular Medicine, New York University School of Medicine, New York, United States.
authors.forename: Sudha
authors.initials: S
authors.lastname: Kumari
authors.affiliation: Skirball Institute of Biomolecular Medicine, New York University School of Medicine, New York, United States.
authors.forename: David
authors.initials: D
authors.lastname: Depoil
authors.affiliation: Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, United States.
authors.forename: Roberta
authors.initials: R
authors.lastname: Martinelli
authors.affiliation: Department of Biological Engineering, Columbia University, New York, United States.
authors.forename: Edward
authors.initials: E
authors.lastname: Judokusumo
authors.affiliation: David H. Koch Institute for Integrative Cancer research, Massachusetts Institute of Technology, Cambridge, United States.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Carmona
authors.affiliation: David H. Koch Institute for Integrative Cancer research, Massachusetts Institute of Technology, Cambridge, United States.
authors.forename: Frank B
authors.initials: FB
authors.lastname: Gertler
authors.affiliation: Department of Biological Engineering, Columbia University, New York, United States.
authors.forename: Lance C
authors.initials: LC
authors.lastname: Kam
authors.affiliation: Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, United States.
authors.forename: Christopher V
authors.initials: CV
authors.lastname: Carman
authors.affiliation: Department of Pathology and Laboratory Medicine, Perelman School of Medicine, The Children's Hospital of Philadelphia, University of Pennsylvania, Philadelphia, United States.
authors.forename: Janis K
authors.initials: JK
authors.lastname: Burkhardt
authors.affiliation: David H. Koch Institute for Integrative Cancer research, Massachusetts Institute of Technology, Cambridge, United States.
authors.forename: Darrell J
authors.initials: DJ
authors.lastname: Irvine
authors.affiliation: Skirball Institute of Biomolecular Medicine, New York University School of Medicine, New York, United States.
authors.forename: Michael L
authors.initials: ML
authors.lastname: Dustin
mesh_terms: D000199:Actins / Q000378:metabolism*; D000818:Animals; D020013:Calcium Signaling; D002478:Cells, Cultured; D004789:Enzyme Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D051966:Phospholipase C gamma / Q000378:metabolism*; D058105:Polymerization; D013601:T-Lymphocytes / Q000201:enzymology* / Q000378:metabolism; D051316:Wiskott-Aldrich Syndrome Protein / Q000378:metabolism*
chemical_list: D000199:Actins; D051316:Wiskott-Aldrich Syndrome Protein; D051966:Phospholipase C gamma
keywords: T cell receptor signaling; actin polymerization; cell biology; human; immunological synapse; immunology; mouse