PKCθ links proximal T cell and Notch signaling through localized regulation of the actin cytoskeleton
- University of Bristol, United Kingdom
- University of Birmingham, United Kingdom
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.
Article and author information
Author details
Lea A Hampton-O'Neil
David Cameron Wraith
Funding
European Research Council (PCIG-GA-2012-321554)
- Christoph Wuelfing
Multiple Sclerosis Society (900/08)
- Catherine Sabatos-Peyton
Wellcome Trust (102387/Z/13/Z)
- Rachel Ambler
- Helen M Tunbridge
- Kerrie E McNally
- Lea A Hampton-O'Neil
Wellcome Trust (091074/Z/09/Z)
- Elaine V Hill
- David Cameron Wraith
University of Bristol (PhD studentship)
- Danielle J Clark
Wellcome Trust (086779/Z/08/A)
- Graham J Britton
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Michael L Dustin, University of Oxford, United Kingdom
Ethics
Animal experimentation: All animal experiments were carried out under the UK Home Office Project Licence number 30/2705 held by David Wraith and the study was approved by the University of Bristol ethical review committee.
Version history
- Received: July 24, 2016
- Accepted: January 22, 2017
- Accepted Manuscript published: January 23, 2017 (version 1)
- Accepted Manuscript updated: January 31, 2017 (version 2)
- Version of Record published: February 15, 2017 (version 3)
- Version of Record updated: April 5, 2017 (version 4)
Copyright
© 2017, Britton et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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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
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