Actin foci facilitate activation of the phospholipase C-γ in primary T lymphocytes via the WASP pathway
Sudha Kumari,
David Depoil,
Roberta Martinelli,
Edward Judokusumo,
Guillaume Carmona,
Frank B Gertler,
Lance C Kam,
Christopher V Carman,
Janis K Burkhardt,
Darrell J Irvine,
Michael L Dustin
Affiliations
Sudha Kumari
Skirball Institute of Biomolecular Medicine, New York University School of Medicine, New York, United States; David H. Koch Institute for Integrative Cancer research, Massachusetts Institute of Technology, Cambridge, United States
David Depoil
Skirball Institute of Biomolecular Medicine, New York University School of Medicine, New York, United States; Nuffield Department of Orthopedics, Rheumatology and Musculosceletal Sciences, University of Oxford, Headington, United Kingdom
Roberta Martinelli
Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, United States
Edward Judokusumo
Department of Biological Engineering, Columbia University, New York, United States
Guillaume Carmona
David H. Koch Institute for Integrative Cancer research, Massachusetts Institute of Technology, Cambridge, United States
Frank B Gertler
David H. Koch Institute for Integrative Cancer research, Massachusetts Institute of Technology, Cambridge, United States
Lance C Kam
Department of Biological Engineering, Columbia University, New York, United States
Christopher V Carman
Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, United States
Janis K Burkhardt
Department of Pathology and Laboratory Medicine, Perelman School of Medicine, The Children's Hospital of Philadelphia, University of Pennsylvania, Philadelphia, United States
Darrell J Irvine
David H. Koch Institute for Integrative Cancer research, Massachusetts Institute of Technology, Cambridge, United States
Skirball Institute of Biomolecular Medicine, New York University School of Medicine, New York, United States; Nuffield Department of Orthopedics, Rheumatology and Musculosceletal Sciences, University of Oxford, Headington, United Kingdom
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.
