Distinct TCR signaling pathways drive proliferation and cytokine production in T cells

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Item Type:	Article
Title:	Distinct TCR signaling pathways drive proliferation and cytokine production in T cells
Creators Name:	Guy, C.S., Vignali, K.M., Temirov, J., Bettini, M.L., Overacre, A.E., Smeltzer, M., Zhang, H., Huppa, J.B., Tsai, Y.H., Lobry, C., Xie, J., Dempsey, P.J., Crawford, H.C., Aifantis, I., Davis, M.M. and Vignali, D.A.A.
Abstract:	The physiological basis and mechanistic requirements for a large number of functional immunoreceptor tyrosine-based activation motifs (ITAMs; high ITAM multiplicity) in the complex of the T cell antigen receptor (TCR) and the invariant signaling protein CD3 remain obscure. Here we found that whereas a low multiplicity of TCR-CD3 ITAMs was sufficient to engage canonical TCR-induced signaling events that led to cytokine secretion, a high multiplicity of TCR-CD3 ITAMs was required for TCR-driven proliferation. This was dependent on the formation of compact immunological synapses, interaction of the adaptor Vav1 with phosphorylated CD3 ITAMs to mediate the recruitment and activation of the oncogenic transcription factor Notch1 and, ultimately, proliferation induced by the cell-cycle regulator c-Myc. Analogous mechanistic events were also needed to drive proliferation in response to weak peptide agonists. Thus, the TCR-driven pathways that initiate cytokine secretion and proliferation are separable and are coordinated by the multiplicity of phosphorylated ITAMs in TCR-CD3.
Keywords:	CD3 Complex, Cell Line, Cell Proliferation, Cytokines, HEK293 Cells, Immunoreceptor Tyrosine-Based Activation Motif, Lymphocyte Activation, Inbred C57BL Mice, Knockout Mice, Phosphorylation, Proto-Oncogene Proteins c-myc, Proto-Oncogene Proteins c-vav, Notch1 Receptor, T-Cell Antigen Receptors, Signal Transduction, T-Lymphocytes, T-Lymphocytes / Metabolism, Animals, Mice
Source:	Nature Immunology
ISSN:	1529-2908
Publisher:	Nature Publishing Group
Volume:	14
Number:	3
Page Range:	262-70
Date:	March 2013
Official Publication:	https://doi.org/10.1038/ni.2538
PubMed:	View item in PubMed

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