title: GADS is required for TCR-mediated calcium influx and cytokine release, but not cellular adhesion, in human T cells.
abstract: GRB2 related adaptor protein downstream of Shc (GADS) is a member of the GRB2 family of adaptors and is critical for TCR-induced signaling. The current model is that GADS recruits SLP-76 to the LAT complex, which facilitates the phosphorylation of SLP-76, the activation of PLC-γ1, T cell adhesion and cytokine production. However, this model is largely based on studies of disruption of the GADS/SLP-76 interaction and murine T cell differentiation in GADS deficient mice. The role of GADS in mediating TCR-induced signals in human CD4+ T cells has not been thoroughly investigated. In this study, we have suppressed the expression of GADS in human CD4+ HuT78 T cells. GADS deficient HuT78 T cells displayed similar levels of TCR-induced SLP-76 and PLC-γ1 phosphorylation but exhibited substantial decrease in TCR-induced IL-2 and IFN-γ release. The defect in cytokine production occurred because of impaired calcium mobilization due to reduced recruitment of SLP-76 and PLC-γ1 to the LAT complex. Surprisingly, both GADS deficient HuT78 and GADS deficient primary murine CD8+ T cells had similar TCR-induced adhesion when compared to control T cells. Overall, our results show that GADS is required for calcium influx and cytokine production, but not cellular adhesion, in human CD4+ T cells, suggesting that the current model for T cell regulation by GADS is incomplete.
authors: Interdisciplinary Graduate Program in Immunology, University of Iowa, Iowa City, IA 52242, United States.
authors: Mahmood Y
authors: MY
authors: Bilal
authors: Department of Microbiology, Molecular Genetics and Immunology, University of Kansas Medical Center, Kansas City, KS 66160, United States.
authors: Elizabeth Y
authors: EY
authors: Zhang
authors: Department of Microbiology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, United States.
authors: Brittney
authors: B
authors: Dinkel
authors: Department of Microbiology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, United States.
authors: Daimon
authors: D
authors: Hardy
authors: Department of Microbiology, Molecular Genetics and Immunology, University of Kansas Medical Center, Kansas City, KS 66160, United States.
authors: Thomas M
authors: TM
authors: Yankee
authors: Interdisciplinary Graduate Program in Immunology, University of Iowa, Iowa City, IA 52242, United States; Department of Microbiology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, United States.
authors: Jon C D
authors: JC
authors: Houtman
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism*; D002448:Cell Adhesion; D002460:Cell Line; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism*; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D007376:Interleukin-2 / Q000378:metabolism; D051379:Mice; D051966:Phospholipase C gamma / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism; D021381:Protein Transport; D034622:RNA Interference; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D016207:Cytokines; C409587:GRAP2 protein, human; D007376:Interleukin-2; D010750:Phosphoproteins; D011948:Receptors, Antigen, T-Cell; C092947:SLP-76 signal Transducing adaptor proteins; D007371:Interferon-gamma; D051966:Phospholipase C gamma; D002118:Calcium
keywords: GRB2 family of adaptors; Human T cells; PLC-γ1; T cell receptor signaling
references: Mol Cell Biol. 2006 Sep;26(17):6727-38
references: 16914752
references: Mol Cell Biol. 2006 Oct;26(19):7155-66
references: 16980618
references: J Biol Chem. 2007 Feb 2;282(5):2937-46
references: 17148460
references: Mol Cell Biol. 2001 Jul;21(13):4208-18
references: 11390650
references: J Immunol. 2007 Jul 15;179(2):1013-21
references: 17617593
references: Eur J Immunol. 2007 Oct;37(10):2961-72
references: 17823979
references: Annu Rev Immunol. 2008;26:233-59
references: 18304005
references: Adv Immunol. 2008;97:1-64
references: 18501768
references: Nature. 2009 Mar 5;458(7234):87-91
references: 19262673
references: PLoS One. 2009;4(5):e5430
references: 19412549
references: Annu Rev Immunol. 2009;27:591-619
references: 19132916
references: Immunity. 2009 Aug 21;31(2):174-6
references: 19699166
references: Cell Signal. 2010 May;22(5):848-56
references: 20079431
references: Nat Immunol. 2010 Apr;11(4):344-9
references: 20208539
references: EMBO J. 2010 Jul 21;29(14):2315-28
references: 20562827
references: Cold Spring Harb Perspect Biol. 2010 Aug;2(8):a005512
references: 20610546
references: FEBS Lett. 2010 Dec 15;584(24):4858-64
references: 20828569
references: J Immunol. 2011 Mar 1;186(5):2926-35
references: 21282515
references: J Immunol. 2011 Apr 15;186(8):4579-89
references: 21411729
references: Mol Cell Biol. 2011 Jul;31(13):2653-66
references: 21536650
references: EMBO J. 2011 Aug 3;30(15):3160-72
references: 21725281
references: Mol Cell Biol. 2011 Nov;31(22):4524-37
references: 21930784
references: PLoS One. 2012;7(12):e53011
references: 23300847
references: Leukemia. 2013 Aug;27(8):1666-76
references: 23399893
references: J Immunol. 2013 Dec 15;191(12):6208-21
references: 24227778
references: Immunity. 1998 Nov;9(5):617-26
references: 9846483
references: J Immunol. 1998 Oct 15;161(8):3880-9
references: 9780153
references: J Immunol. 2004 Aug 1;173(3):1711-20
references: 15265900
references: J Biol Chem. 2004 Apr 9;279(15):15481-90
references: 14722089
references: J Immunol. 2003 Aug 1;171(3):1360-8
references: 12874226
references: RNA. 2003 Apr;9(4):493-501
references: 12649500
references: J Allergy Clin Immunol. 2002 May;109(5):758-70
references: 11994696
references: J Immunol. 2002 Feb 15;168(4):1557-65
references: 11823482
references: Oncogene. 2001 Oct 1;20(44):6284-90
references: 11607830
references: Mol Cell Biol. 2006 Mar;26(5):1826-38
references: 16479002
references: J Immunol. 2005 Aug 15;175(4):2449-58
references: 16081816
references: Eur J Immunol. 2005 Apr;35(4):1184-92
references: 15761845
references: J Biol Chem. 2005 Mar 4;280(9):8364-70
references: 15623534
references: Nat Immunol. 2005 Jan;6(1):80-9
references: 15558067
references: Nat Immunol. 2014 Apr;15(4):384-92
references: 24584089
references: J Exp Med. 1999 May 3;189(9):1383-90
references: 10224278
references: Int Immunol. 1999 Jun;11(6):943-50
references: 10360968
references: J Biol Chem. 2000 Jul 21;275(29):21946-52
references: 10781580
references: Mol Cell Biol. 2000 Dec;20(24):9149-61
references: 11094067
references: Science. 2001 Mar 9;291(5510):1987-91
references: 11239162
references: Immunity. 2001 Mar;14(3):315-29
references: 11290340
references: J Exp Med. 1999 Apr 19;189(8):1243-53
references: 10209041
references: Curr Biol. 1999 Jan 28;9(2):67-75
references: 10021361
references: Proc Natl Acad Sci U S A. 2007 Apr 17;104(16):6638-43
references: 17420479