LFA-1 regulates CD8+ T cell activation via T cell receptor-mediated and LFA-1-mediated Erk1/2 signal pathways

J Biol Chem. 2009 Jul 31;284(31):21001-10. doi: 10.1074/jbc.M109.002865. Epub 2009 May 29.

Abstract

LFA-1 regulates T cell activation and signal transduction through the immunological synapse. T cell receptor (TCR) stimulation rapidly activates LFA-1, which provides unique LFA-1-dependent signals to promote T cell activation. However, the detailed molecular pathways that regulate these processes and the precise mechanism by which LFA-1 contributes to TCR activation remain unclear. We found LFA-1 directly participates in Erk1/2 signaling upon TCR stimulation in CD8+ T cells. The presence of LFA-1, not ligand binding, is required for the TCR-mediated Erk1/2 signal pathway. LFA-1-deficient T cells have defects in sustained Erk1/2 signaling and TCR/CD3 clustering, which subsequently prevents MTOC reorientation, cell cycle progression, and mitosis. LFA-1 regulates the TCR-mediated Erk1/2 signal pathway in the context of immunological synapse for recruitment and amplification of the Erk1/2 signal. In addition, LFA-1 ligation with ICAM-1 generates an additional Erk1/2 signal, which synergizes with the existing TCR-mediated Erk1/2 signal to enhance T cell activation. Thus, LFA-1 contributes to CD8+ T cell activation through two distinct signal pathways. We demonstrated that the function of LFA-1 is to enhance TCR signaling through the immunological synapse and deliver distinct signals in CD8+ T cell activation.

MeSH terms

  • Animals
  • CD3 Complex / immunology
  • CD8-Positive T-Lymphocytes / cytology
  • CD8-Positive T-Lymphocytes / enzymology*
  • CD8-Positive T-Lymphocytes / immunology
  • Cell Proliferation
  • Intercellular Adhesion Molecule-1 / metabolism
  • Lymphocyte Activation / immunology*
  • Lymphocyte Function-Associated Antigen-1 / immunology*
  • MAP Kinase Signaling System*
  • Mice
  • Microtubule-Organizing Center / metabolism
  • Mitogen-Activated Protein Kinase 1 / metabolism*
  • Mitogen-Activated Protein Kinase 3 / metabolism*
  • Mitosis
  • Receptors, Antigen, T-Cell / immunology*

Substances

  • CD3 Complex
  • Lymphocyte Function-Associated Antigen-1
  • Receptors, Antigen, T-Cell
  • Intercellular Adhesion Molecule-1
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3