title: MTOC translocation modulates IS formation and controls sustained T cell signaling.
abstract: The translocation of the microtubule-organizing center (MTOC) toward the nascent immune synapse (IS) is an early step in lymphocyte activation initiated by T cell receptor (TCR) signaling. The molecular mechanisms that control the physical movement of the lymphocyte MTOC remain largely unknown. We have studied the role of the dynein-dynactin complex, a microtubule-based molecular motor, in the process of T cell activation during T cell antigen-presenting cell cognate immune interactions. Impairment of dynein-dynactin complex activity, either by overexpressing the p50-dynamitin component of dynactin to disrupt the complex or by knocking down dynein heavy chain expression to prevent its formation, inhibited MTOC translocation after TCR antigen priming. This resulted in a strong reduction in the phosphorylation of molecules such as zeta chain-associated protein kinase 70 (ZAP70), linker of activated T cells (LAT), and Vav1; prevented the supply of molecules to the IS from intracellular pools, resulting in a disorganized and dysfunctional IS architecture; and impaired interleukin-2 production. Together, these data reveal MTOC translocation as an important mechanism underlying IS formation and sustained T cell signaling.
authors.affiliation: Servicio de Inmunología, Hospital de la Princesa, Universidad Autónoma de Madrid, 28006 Madrid, Spain.
authors.forename: Noa B
authors.initials: NB
authors.lastname: Martín-Cófreces
authors.forename: Javier
authors.initials: J
authors.lastname: Robles-Valero
authors.forename: J Román
authors.initials: JR
authors.lastname: Cabrero
authors.forename: María
authors.initials: M
authors.lastname: Mittelbrunn
authors.forename: Mónica
authors.initials: M
authors.lastname: Gordón-Alonso
authors.forename: Ching-Hwa
authors.initials: CH
authors.lastname: Sung
authors.forename: Balbino
authors.initials: B
authors.lastname: Alarcón
authors.forename: Jesús
authors.initials: J
authors.lastname: Vázquez
authors.forename: Francisco
authors.initials: F
authors.lastname: Sánchez-Madrid
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000938:Antigen-Presenting Cells / Q000276:immunology; D001692:Biological Transport / Q000276:immunology; D017252:CD3 Complex / Q000276:immunology; D002460:Cell Line; D000072159:Dynactin Complex; D004398:Dyneins / Q000037:antagonists & inhibitors / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000032:analysis; D006801:Humans; D007376:Interleukin-2 / Q000378:metabolism; D019169:Jurkat Cells; D008213:Lymphocyte Activation; D016169:Lymphocyte Function-Associated Antigen-1 / Q000276:immunology; D008565:Membrane Proteins / Q000378:metabolism; D008869:Microtubule-Associated Proteins / Q000032:analysis / Q000378:metabolism; D022101:Microtubule-Organizing Center / Q000276:immunology* / Q000648:ultrastructure; D010766:Phosphorylation; D021122:Protein Subunits / Q000276:immunology; D034622:RNA Interference; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D017252:CD3 Complex; C000606361:DCTN2 protein, human; D000072159:Dynactin Complex; D007376:Interleukin-2; C110810:LAT protein, human; D016169:Lymphocyte Function-Associated Antigen-1; D008565:Membrane Proteins; D008869:Microtubule-Associated Proteins; D021122:Protein Subunits; D011948:Receptors, Antigen, T-Cell; D049452:Green Fluorescent Proteins; D004398:Dyneins
references.citation: J Cell Sci. 2004 Mar 1;117(Pt 7):1009-16
references.pmid: 14996932
references.citation: J Exp Med. 1992 Jun 1;175(6):1493-9
references.pmid: 1588277
references.citation: Nature. 1998 Sep 3;395(6697):82-6
references.pmid: 9738502
references.citation: Proc Natl Acad Sci U S A. 1991 Feb 1;88(3):775-9
references.pmid: 1825141
references.citation: Curr Biol. 1998 Apr 23;8(9):541-4
references.pmid: 9560347
references.citation: J Neurobiol. 2004 Feb 5;58(2):189-200
references.pmid: 14704951
references.citation: Proc Natl Acad Sci U S A. 2006 Oct 3;103(40):14883-8
references.pmid: 16990435
references.citation: J Neurosci. 2004 Mar 3;24(9):2304-12
references.pmid: 14999081
references.citation: J Exp Med. 1987 Jun 1;165(6):1565-80
references.pmid: 2953845
references.citation: Nat Rev Immunol. 2007 Feb;7(2):131-43
references.pmid: 17259969
references.citation: Immunol Rev. 2002 Nov;189:84-97
references.pmid: 12445267
references.citation: Immunity. 2001 Nov;15(5):751-61
references.pmid: 11728337
references.citation: Immunol Rev. 2007 Aug;218:147-64
references.pmid: 17624951
references.citation: Science. 1998 Jan 23;279(5350):519-26
references.pmid: 9438838
references.citation: Nat Cell Biol. 2006 Jun;8(6):562-70
references.pmid: 16715075
references.citation: J Immunol. 2006 Jun 15;176(12):7243-53
references.pmid: 16751367
references.citation: Cell. 1998 Sep 4;94(5):667-77
references.pmid: 9741631
references.citation: J Cell Biol. 1995 Dec;131(6 Pt 1):1507-16
references.pmid: 8522607
references.citation: Science. 2000 Mar 24;287(5461):2260-2
references.pmid: 10731147
references.citation: J Immunol. 1982 Mar;128(3):1159-62
references.pmid: 7035558
references.citation: Nat Rev Immunol. 2004 Feb;4(2):110-22
references.pmid: 15040584
references.citation: J Cell Biol. 1996 Feb;132(4):617-33
references.pmid: 8647893
references.citation: J Immunol. 2005 Aug 15;175(4):2449-58
references.pmid: 16081816
references.citation: J Cell Sci. 2006 Nov 1;119(Pt 21):4369-71
references.pmid: 17074830
references.citation: Biochim Biophys Acta. 2005 Jul 10;1744(3):316-24
references.pmid: 15950296
references.citation: Proc Natl Acad Sci U S A. 2000 Sep 26;97(20):10923-9
references.pmid: 11005864
references.citation: J Exp Med. 1989 Nov 1;170(5):1697-713
references.pmid: 2530300
references.citation: J Cell Biol. 2003 Sep 15;162(6):963-9
references.pmid: 12975343
references.citation: Mol Cell Biol. 2000 Mar;20(5):1678-91
references.pmid: 10669745
references.citation: Trends Cell Biol. 2005 Jun;15(6):288-94
references.pmid: 15953546
references.citation: J Immunol. 1984 Nov;133(5):2762-6
references.pmid: 6384372
references.citation: J Biol Chem. 2007 Jul 6;282(27):19355-64
references.pmid: 17449914
references.citation: J Immunol. 1999 Feb 1;162(3):1367-75
references.pmid: 9973391
references.citation: J Immunol. 2002 Jul 1;169(1):292-300
references.pmid: 12077257
references.citation: J Cell Biol. 1998 Feb 23;140(4):861-71
references.pmid: 9472038
references.citation: J Immunol. 1997 Aug 15;159(4):1703-10
references.pmid: 9257831
references.citation: Nature. 2006 Sep 28;443(7110):462-5
references.pmid: 17006514
references.citation: Eur J Immunol. 2003 Mar;33(3):790-7
references.pmid: 12616499
references.citation: J Exp Med. 1994 May 1;179(5):1507-15
references.pmid: 7513010
references.citation: J Immunol. 2006 Apr 1;176(7):4201-7
references.pmid: 16547257
references.citation: Mol Biol Cell. 2003 Dec;14(12):5089-97
references.pmid: 14565986
references.citation: Immunity. 2002 Mar;16(3):331-43
references.pmid: 11911819
references.citation: Science. 2003 Nov 14;302(5648):1218-22
references.pmid: 14512504
references.citation: Immunol Rev. 2002 Nov;189:123-35
references.pmid: 12445270
references.citation: J Biol Chem. 2000 Aug 25;275(34):26436-40
references.pmid: 10840040
references.citation: Curr Biol. 2001 Oct 2;11(19):1536-41
references.pmid: 11591323
references.citation: J Mol Cell Immunol. 1985;2(1):37-49
references.pmid: 3880506
references.citation: Immunity. 2004 Apr;20(4):417-28
references.pmid: 15084271
references.citation: J Exp Med. 2005 Jul 4;202(1):181-92
references.pmid: 15998796
references.citation: Proc Natl Acad Sci U S A. 1997 Jul 8;94(14):7493-8
references.pmid: 9207119
references.citation: Science. 1999 Jul 9;285(5425):221-7
references.pmid: 10398592
references.citation: Biochem J. 2001 Jun 1;356(Pt 2):461-71
references.pmid: 11368773
references.citation: Curr Biol. 1999 Apr 22;9(8):425-8
references.pmid: 10226031
references.citation: J Cell Biol. 1994 May;125(3):639-49
references.pmid: 7513706
references.citation: Immunity. 2002 Oct;17(4):389-99
references.pmid: 12387734
references.citation: J Exp Med. 1997 May 19;185(10):1877-82
references.pmid: 9151714
references.citation: J Exp Med. 2004 Oct 18;200(8):1063-74
references.pmid: 15477347
references.citation: J Cell Sci. 2003 Sep 15;116(Pt 18):3793-802
references.pmid: 12902405