Cytotoxic-T-lymphocyte antigen 4 receptor signaling for lymphocyte adhesion is mediated by C3G and Rap1

Mol Cell Biol. 2014 Mar;34(6):978-88. doi: 10.1128/MCB.01024-13. Epub 2014 Jan 6.

Abstract

T-lymphocyte adhesion plays a critical role in both inflammatory and autoimmune responses. The small GTPase Rap1 is the key coordinator mediating T-cell adhesion to endothelial cells, antigen-presenting cells, and virus-infected cells. We describe a signaling pathway, downstream of the cytotoxic T-lymphocyte antigen 4 (CTLA-4) receptor, leading to Rap1-mediated adhesion. We identified a role for the Rap1 guanine nucleotide exchange factor C3G in the regulation of T-cell adhesion and showed that this factor is required for both T-cell receptor (TCR)-mediated and CTLA-4-mediated T-cell adhesion. Our data indicated that C3G translocates to the plasma membrane downstream of TCR signaling, where it regulates activation of Rap1. We also showed that CTLA-4 receptor signaling mediates tyrosine phosphorylation in the C3G protein, and that this is required for augmented activation of Rap1 and increased adhesion mediated by leukocyte function-associated antigen type 1 (LFA-1). Zap70 is required for C3G translocation to the plasma membrane, whereas the Src family member Hck facilitates C3G phosphorylation. These findings point to C3G and Hck as promising potential therapeutic targets for the treatment of T-cell-dependent autoimmune disorders.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CD28 Antigens / genetics
  • CD28 Antigens / metabolism
  • CTLA-4 Antigen / genetics
  • CTLA-4 Antigen / metabolism*
  • Cell Adhesion / genetics
  • Cell Adhesion / physiology*
  • Cell Line, Tumor
  • Cell Membrane / genetics
  • Cell Membrane / metabolism
  • Female
  • Genes, src / genetics
  • Guanine Nucleotide-Releasing Factor 2 / genetics
  • Guanine Nucleotide-Releasing Factor 2 / metabolism*
  • Humans
  • Jurkat Cells
  • Lymphocyte Function-Associated Antigen-1 / genetics
  • Lymphocyte Function-Associated Antigen-1 / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Phosphorylation / genetics
  • Phosphorylation / physiology
  • Proto-Oncogene Proteins c-hck / genetics
  • Proto-Oncogene Proteins c-hck / metabolism
  • Signal Transduction / genetics
  • Signal Transduction / physiology*
  • T-Lymphocytes / metabolism
  • rap1 GTP-Binding Proteins / genetics
  • rap1 GTP-Binding Proteins / metabolism*
  • ras Proteins / genetics
  • ras Proteins / metabolism

Substances

  • CD28 Antigens
  • CTLA-4 Antigen
  • Guanine Nucleotide-Releasing Factor 2
  • Lymphocyte Function-Associated Antigen-1
  • Proto-Oncogene Proteins c-hck
  • rap1 GTP-Binding Proteins
  • ras Proteins