title: IGSF4 is a novel TCR ζ-chain-interacting protein that enhances TCR-mediated signaling.
abstract: Immunoglobulin superfamily member 4 (IGSF4) is a known ligand of CRTAM, a receptor expressed in activated NKT and CD8(+) T cells, but its function in T cell immunity has not been elucidated. In this study, we show that IGSF4 directly interacts with the T cell receptor (TCR) ζ-chain and enhances TCR signaling by enhancing ζ-chain phosphorylation. Ectopic overexpression of IGSF4 enhances TCR-mediated T cell activation. In contrast, IGSF4 knockdown shows a dramatic decrease in markers associated with T cell activation compared with those in control small interfering RNA. The transmembrane domain is essential for TCR ζ-chain association and clustering to the immunological synapse, and the ectodomain is associated with T cell interaction with antigen-presenting cells (APCs). IGSF4-deficient mice have impaired TCR-mediated thymocyte selection and maturation. Furthermore, these mice reveal attenuated effector T cell functions accompanied by defective TCR signaling. Collectively, the results indicate that IGSF4 plays a central role in T cell functioning by dual independent mechanisms, control of TCR signaling and control of T cell-APC interaction.
authors.affiliation: Immune Synapse Research Center, School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju 500-712, South Korea.
authors.forename: Hye-Ran
authors.initials: HR
authors.lastname: Kim
authors.forename: Byeong-Hun
authors.initials: BH
authors.lastname: Jeon
authors.forename: Hyun-Su
authors.initials: HS
authors.lastname: Lee
authors.forename: Sin-Hyeog
authors.initials: SH
authors.lastname: Im
authors.forename: Masatake
authors.initials: M
authors.lastname: Araki
authors.forename: Kimi
authors.initials: K
authors.lastname: Araki
authors.forename: Ken-ichi
authors.initials: K
authors.lastname: Yamamura
authors.forename: Suck-Chei
authors.initials: SC
authors.lastname: Choi
authors.forename: Do-Sim
authors.initials: DS
authors.lastname: Park
authors.forename: Chang-Duk
authors.initials: CD
authors.lastname: Jun
mesh_terms: D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology*; D015153:Blotting, Western; D000075982:Cell Adhesion Molecule-1; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism*; D017931:DNA Primers / Q000235:genetics; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D055785:Gene Knockdown Techniques; D006801:Humans; D007111:Immunity, Cellular / Q000276:immunology*; D007136:Immunoglobulins / Q000235:genetics / Q000378:metabolism*; D047468:Immunoprecipitation; D019169:Jurkat Cells; D008213:Lymphocyte Activation / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008856:Microscopy, Fluorescence; D010766:Phosphorylation; D034741:RNA, Small Interfering / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: C498598:Cadm1 protein, mouse; D000075982:Cell Adhesion Molecule-1; D015815:Cell Adhesion Molecules; D017931:DNA Primers; D007136:Immunoglobulins; D034741:RNA, Small Interfering; D011948:Receptors, Antigen, T-Cell; C054979:antigen T cell receptor, zeta chain
references.citation: Sci STKE. 2000 Dec 19;2000(63):re1
references.pmid: 11752630
references.citation: Semin Immunol. 2000 Feb;12(1):35-41
references.pmid: 10723796
references.citation: J Immunol. 2001 Oct 1;167(7):3715-24
references.pmid: 11564787
references.citation: Brain Res Dev Brain Res. 2005 Apr 21;156(1):23-31
references.pmid: 15862624
references.citation: Cancer Sci. 2005 Sep;96(9):543-52
references.pmid: 16128739
references.citation: Dev Immunol. 2000;7(2-4):179-93
references.pmid: 11097211
references.citation: Blood. 2000 Sep 15;96(6):2181-90
references.pmid: 10979964
references.citation: Blood. 2003 Apr 1;101(7):2601-8
references.pmid: 12456501
references.citation: Curr Top Microbiol Immunol. 2010;340:81-107
references.pmid: 19960310
references.citation: Protein Eng. 1990 Mar;3(4):245-8
references.pmid: 2160658
references.citation: J Exp Med. 1998 Aug 3;188(3):561-75
references.pmid: 9687533
references.citation: Crit Rev Immunol. 1995;15(3-4):235-53
references.pmid: 8834450
references.citation: Science. 2002 Aug 30;297(5586):1525-31
references.pmid: 12202822
references.citation: J Cell Sci. 2001 Jan;114(Pt 2):243-4
references.pmid: 11148124
references.citation: J Exp Med. 1998 Dec 21;188(12):2301-11
references.pmid: 9858516
references.citation: Cell. 2008 Mar 7;132(5):846-59
references.pmid: 18329370
references.citation: J Exp Med. 2001 Jun 4;193(11):1269-84
references.pmid: 11390434
references.citation: J Immunol. 1991 May 15;146(10):3273-9
references.pmid: 1673979
references.citation: Mol Cell Biol. 2006 May;26(9):3595-609
references.pmid: 16611999
references.citation: Oncogene. 2003 Sep 18;22(40):6160-5
references.pmid: 13679854
references.citation: Nature. 1992 Nov 19;360(6401):225-31
references.pmid: 1359428
references.citation: Med Sci (Paris). 2007 Feb;23(2):161-6
references.pmid: 17291425
references.citation: Biochem Biophys Res Commun. 2004 Jun 18;319(1):200-6
references.pmid: 15158462
references.citation: Lab Invest. 2005 Mar;85(3):426-35
references.pmid: 15654360
references.citation: J Immunol. 1999 Oct 1;163(7):3867-76
references.pmid: 10490986
references.citation: Nature. 1998 Sep 3;395(6697):82-6
references.pmid: 9738502
references.citation: J Biol Chem. 2003 Sep 12;278(37):35421-7
references.pmid: 12826663
references.citation: J Exp Med. 2003 Nov 17;198(10):1463-73
references.pmid: 14610044
references.citation: Int Immunol. 2005 Sep;17(9):1227-37
references.pmid: 16091383
references.citation: Blood. 2005 Feb 1;105(3):1204-13
references.pmid: 15471956
references.citation: J Biol Chem. 2010 Apr 23;285(17):13022-31
references.pmid: 20178993
references.citation: Nat Rev Immunol. 2004 Aug;4(8):603-16
references.pmid: 15286727
references.citation: Nat Immunol. 2002 Feb;3(2):159-68
references.pmid: 11812993
references.citation: Proc Natl Acad Sci U S A. 1992 Apr 1;89(7):2945-9
references.pmid: 1372996
references.citation: Mol Cell Biol. 2006 May;26(9):3610-24
references.pmid: 16612000
references.citation: J Exp Med. 1985 Sep 1;162(3):802-22
references.pmid: 2863322
references.citation: Histol Histopathol. 2003 Oct;18(4):1321-9
references.pmid: 12973698
references.citation: Mol Cell Biol. 2003 Mar;23(6):2017-28
references.pmid: 12612075
references.citation: J Immunol. 2008 Feb 1;180(3):1634-42
references.pmid: 18209059
references.citation: Curr Opin Immunol. 1997 Jun;9(3):380-9
references.pmid: 9203416
references.citation: Immunity. 2001 Nov;15(5):691-701
references.pmid: 11728332
references.citation: Genes Immun. 2005 Jun;6(4):319-31
references.pmid: 15789058
references.citation: Curr Opin Immunol. 1992 Apr;4(2):140-6
references.pmid: 1351392
references.citation: J Immunol. 2005 Dec 15;175(12):7947-56
references.pmid: 16339530
references.citation: J Exp Med. 1999 Apr 19;189(8):1181-94
references.pmid: 10209036
references.citation: J Exp Med. 2002 Dec 16;196(12):1617-26
references.pmid: 12486104
references.citation: Science. 1999 Jul 9;285(5425):221-7
references.pmid: 10398592
references.citation: J Cell Biochem. 2010 Sep 1;111(1):111-22
references.pmid: 20556794