期刊
ELIFE
卷 6, 期 -, 页码 -出版社
ELIFE SCIENCES PUBLICATIONS LTD
DOI: 10.7554/eLife.20003
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资金
- European Research Council [PCIG-GA-2012-321554]
- Multiple Sclerosis Society [900/08]
- Wellcome Trust [102387/Z/13/Z, 091074/Z/09/Z, 086779/Z/08/A]
- University of Bristol
- Biotechnology and Biological Sciences Research Council [BB/L014181/1] Funding Source: researchfish
- BBSRC [BB/L014181/1] Funding Source: UKRI
- Wellcome Trust [102387/Z/13/Z, 086779/Z/08/A, 091074/Z/09/Z] Funding Source: Wellcome Trust
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 PKC theta is a critical mediator of signaling by the T cell antigen receptor and the principal costimulatory receptor CD28. PKC theta 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.
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