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

Research output: Contribution to journalArticlepeer-review

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-Peyton
  • Lea A Hampton-O'Neil
  • Paul Verkade
  • Christoph Wuelfing

Colleges, School and Institutes

External organisations

  • BRISTOL UNIVERSITY

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.

Details

Original languageEnglish
Article numbere20003
JournalElife
Volume6
Publication statusPublished - 31 Jan 2017

Keywords

  • Journal Article