IGSF4 is a novel TCR ζ-chain-interacting protein that enhances TCR-mediated signaling

J Exp Med. 2011 Nov 21;208(12):2545-60. doi: 10.1084/jem.20110853. Epub 2011 Nov 14.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigen-Presenting Cells / immunology*
  • Blotting, Western
  • Cell Adhesion Molecule-1
  • Cell Adhesion Molecules / genetics
  • Cell Adhesion Molecules / metabolism*
  • DNA Primers / genetics
  • Enzyme-Linked Immunosorbent Assay
  • Flow Cytometry
  • Gene Knockdown Techniques
  • Humans
  • Immunity, Cellular / immunology*
  • Immunoglobulins / genetics
  • Immunoglobulins / metabolism*
  • Immunoprecipitation
  • Jurkat Cells
  • Lymphocyte Activation / immunology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Microscopy, Fluorescence
  • Phosphorylation
  • RNA, Small Interfering / genetics
  • Real-Time Polymerase Chain Reaction
  • Receptors, Antigen, T-Cell / metabolism*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction / immunology*
  • T-Lymphocytes / immunology*


  • Cadm1 protein, mouse
  • Cell Adhesion Molecule-1
  • Cell Adhesion Molecules
  • DNA Primers
  • Immunoglobulins
  • RNA, Small Interfering
  • Receptors, Antigen, T-Cell
  • antigen T cell receptor, zeta chain