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

被引:173
作者
Guy, Clifford S. [1 ]
Vignali, Kate M. [1 ]
Temirov, Jamshid [2 ]
Bettini, Matthew L. [1 ]
Overacre, Abigail E. [1 ]
Smeltzer, Matthew [3 ]
Zhang, Hui [3 ]
Huppa, Johannes B. [4 ]
Tsai, Yu-Hwai [5 ]
Lobry, Camille [6 ,7 ]
Xie, Jianming [8 ]
Dempsey, Peter J. [5 ]
Crawford, Howard C. [9 ]
Aifantis, Iannis [6 ,7 ]
Davis, Mark M. [8 ]
Vignali, Dario A. A. [1 ]
机构
[1] St Jude Childrens Res Hosp, Dept Immunol, Memphis, TN 38105 USA
[2] St Jude Childrens Res Hosp, Memphis, TN 38105 USA
[3] St Jude Childrens Res Hosp, Dept Biostat, Memphis, TN 38105 USA
[4] Med Univ Vienna, Ctr Pathophysiol Infectiol & Immunol, Inst Hyg & Appl Immunol, Immune Recognit Unit, Vienna, Austria
[5] Univ Michigan, Dept Pediat & Communicable Dis, Ann Arbor, MI 48109 USA
[6] NYU, Sch Med, Dept Pathol, Howard Hughes Med Inst, New York, NY USA
[7] NYU, NYU Canc Inst, New York, NY USA
[8] Stanford Sch Med, Dept Microbiol & Immunol, Howard Hughes Med Inst, Palo Alto, CA USA
[9] Mayo Clin, Ctr Canc, Dept Canc Biol, Jacksonville, FL 32224 USA
基金
美国国家卫生研究院;
关键词
IN-VIVO; ADAPTER PROTEINS; C-MYC; NOTCH; ACTIVATION; ACTIN; LINKS; VAV; NCK; MICROCLUSTERS;
D O I
10.1038/ni.2538
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
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.
引用
收藏
页码:262 / 270
页数:9
相关论文
共 44 条
[1]   Notch signaling augments T cell responsiveness by enhancing CD25 expression [J].
Adler, SH ;
Chiffoleau, E ;
Xu, LW ;
Dalton, NM ;
Burg, JM ;
Wells, AD ;
Wolfe, MS ;
Turka, LA ;
Pear, WS .
JOURNAL OF IMMUNOLOGY, 2003, 171 (06) :2896-2903
[2]   Instruction of distinct CD4 T helper cell fates by different notch ligands on antigen-presenting cells [J].
Amsen, D ;
Blander, JM ;
Lee, GR ;
Tanigaki, K ;
Honjo, T ;
Flavell, RA .
CELL, 2004, 117 (04) :515-526
[3]   The Notch regulator Numb links the Notch and TCR signaling pathways [J].
Anderson, AC ;
Kitchens, EA ;
Chan, SW ;
Hill, CS ;
Jan, YN ;
Zhong, WM ;
Robey, EA .
JOURNAL OF IMMUNOLOGY, 2005, 174 (02) :890-897
[4]   Multicolor super-resolution imaging with photo-switchable fluorescent probes [J].
Bates, Mark ;
Huang, Bo ;
Dempsey, Graham T. ;
Zhuang, Xiaowei .
SCIENCE, 2007, 317 (5845) :1749-1753
[5]   Notch signalling: a simple pathway becomes complex [J].
Bray, Sarah J. .
NATURE REVIEWS MOLECULAR CELL BIOLOGY, 2006, 7 (09) :678-689
[6]   The Nck family of adapter proteins:: Regulators of actin cytoskeleton [J].
Buday, L ;
Wunderlich, L ;
Tamás, P .
CELLULAR SIGNALLING, 2002, 14 (09) :723-731
[7]   Actin and agonist MHC-peptide complex-dependent T cell receptor microclusters as scaffolds for signaling [J].
Campi, G ;
Varma, R ;
Dustin, ML .
JOURNAL OF EXPERIMENTAL MEDICINE, 2005, 202 (08) :1031-1036
[8]   ZAP-70 - A 70 KD PROTEIN-TYROSINE KINASE THAT ASSOCIATES WITH THE TCR ZETA-CHAIN [J].
CHAN, AC ;
IWASHIMA, M ;
TURCK, CW ;
WEISS, A .
CELL, 1992, 71 (04) :649-662
[9]   Kuz and TACE can activate Notch independent of ligand [J].
Delwig, A. ;
Rand, M. D. .
CELLULAR AND MOLECULAR LIFE SCIENCES, 2008, 65 (14) :2232-2243
[10]   Defining the specific physiological requirements for c-Myc in T cell development [J].
Douglas, NC ;
Jacobs, H ;
Bothwell, ALM ;
Hayday, AC .
NATURE IMMUNOLOGY, 2001, 2 (04) :307-315