PKCθ links proximal T cell and Notch signaling through localized regulation of the actin cytoskeleton

• DOI: 10.7554/elife.20003
• Publication Date: 2017-01-23T13:00:25Z
• Authors: Graham J Britton; Rachel Ambler; Danielle J Clark; Elaine V Hill; Helen M Tunbridge; Kerrie E McNally; Bronwen R Burton; Philomena Butterweck; Catherine Sabatos...; Lea A Hampton-O’Neil; Paul Verkade; Christoph Wülfing; David Cameron Wraith
• Keywords: 0301 basic medicine; 570; QH301-705.5; Science; T-Lymphocytes; Receptors, Antigen, T-Cell; 610; ADAM10 Protein; Mice; 03 medical and health sciences; CD28 Antigens; Animals; Biology (General); Receptors, Notch; Q; Microfilament Proteins; R; Membrane Proteins; cell signalling; cytoskeleton; CD4 T cell; Cell Biology; 3. Good health; Actin Cytoskeleton; Protein Kinase C-theta; Medicine; Amyloid Precursor Protein Secretases; Signal Transduction

Notch is a critical regulator of T cell differentiation and is activated through proteolytic cleavage in response to ligand engagement. Using murine myelin-reactive CD4 T cells, we demonstrate that proximal T cell signaling modulates Notch activation by a spatiotemporally constrained mechanism. The protein kinase PKCθ is a critical mediator of signaling by the T cell antigen receptor and the principal costimulatory receptor CD28. PKCθ selectively inactivates the negative regulator of F-actin generation, Coronin 1A, at the center of the T cell interface with the antigen presenting cell (APC). This allows for effective generation of the large actin-based lamellum required for recruitment of the Notch-processing membrane metalloproteinase ADAM10. Such enhancement of Notch activation is critical for efficient T cell proliferation and Th17 differentiation. We reveal a novel mechanism that, through modulation of the cytoskeleton, controls Notch activation at the T cell:APC interface thereby linking T cell receptor and Notch signaling pathways.