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

Graham Britton, Rachel C J Ambler, Danielle Clark, Elaine Hill, Helen Tunbridge, Kerrie McNally, Bronwen Burton, Philomena Butterweck, Catherine Sabatos-Peyton, Lea Hampton-O'Neil, Paul Verkade, Christoph Wuelfing, David Wraith

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Abstract

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.
Original languageEnglish
Article numbere20003
Number of pages18
JournaleLife
Volume6
DOIs
Publication statusPublished - 23 Jan 2017

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    Britton, G., Ambler, R. C. J., Clark, D., Hill, E., Tunbridge, H., McNally, K., Burton, B., Butterweck, P., Sabatos-Peyton, C., Hampton-O'Neil, L., Verkade, P., Wuelfing, C., & Wraith, D. (2017). PKCθ links proximal T cell and Notch signaling through localized regulation of the actin cytoskeleton. eLife, 6, [e20003]. https://doi.org/10.7554/eLife.20003