title: Distinct TCR signaling pathways drive proliferation and cytokine production in T cells.
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.
authors: Department of Immunology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors: Clifford S
authors: CS
authors: Guy
authors: Kate M
authors: KM
authors: Vignali
authors: Jamshid
authors: J
authors: Temirov
authors: Matthew L
authors: ML
authors: Bettini
authors: Abigail E
authors: AE
authors: Overacre
authors: Matthew
authors: M
authors: Smeltzer
authors: Hui
authors: H
authors: Zhang
authors: Johannes B
authors: JB
authors: Huppa
authors: Yu-Hwai
authors: YH
authors: Tsai
authors: Camille
authors: C
authors: Lobry
authors: Jianming
authors: J
authors: Xie
authors: Peter J
authors: PJ
authors: Dempsey
authors: Howard C
authors: HC
authors: Crawford
authors: Iannis
authors: I
authors: Aifantis
authors: Mark M
authors: MM
authors: Davis
authors: Dario A A
authors: DA
authors: Vignali
mesh_terms: D000818:Animals; D017252:CD3 Complex / Q000276:immunology* / Q000378:metabolism; D002460:Cell Line; D049109:Cell Proliferation; D016207:Cytokines / Q000096:biosynthesis*; D057809:HEK293 Cells; D006801:Humans; D061625:Immunoreceptor Tyrosine-Based Activation Motif / Q000276:immunology*; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010766:Phosphorylation; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D051567:Proto-Oncogene Proteins c-vav / Q000378:metabolism; D051881:Receptor, Notch1 / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000276:immunology* / Q000378:metabolism; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism
chemical_list: D017252:CD3 Complex; D016207:Cytokines; C489428:Myc protein, mouse; C497762:Notch1 protein, mouse; D016271:Proto-Oncogene Proteins c-myc; D051567:Proto-Oncogene Proteins c-vav; D051881:Receptor, Notch1; D011948:Receptors, Antigen, T-Cell; C496619:Vav1 protein, mouse
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