Human T Cell Activation Induces Synaptic Translocation and Alters Expression of the Serine Protease Inhibitor Neuroserpin and Its Target Protease

J Leukoc Biol. 2015 Apr;97(4):699-710. doi: 10.1189/jlb.1A0814-392R. Epub 2015 Feb 10.

Abstract

Contact between T cells and APCs and activation of an effective immune response trigger cellular polarization and the formation of a structured interface known as the immunological synapse. Interactions across the synapse and secretion of T cell and APC-derived factors into the perisynaptic compartment regulate synapse formation and activation of T cells. We report that the serine protease inhibitor neuroserpin, an axonally secreted protein thought to play roles in the formation of the neuronal synapse and refinement of synaptic activity, is expressed in human naïve effector memory and central memory subsets of CD4(+) and CD8(+) T cells, as well as monocytes, B cells, and NK cells. Neuroserpin partially colocalized with a TGN38/LFA-1-positive vesicle population in T cells and translocates to the immunological synapse upon activation with TCR antibodies or antigen-pulsed APCs. Activation of T cells triggered neuroserpin secretion, a rapid, 8.4-fold up-regulation of the serine protease tissue plasminogen activator, the protease target for neuroserpin, and a delayed, 6.25-fold down-regulation of neuroserpin expression. Evidence of polarization and regulated neuroserpin expression was also seen in ex vivo analyses of human lymph nodes and blood-derived T cells. Increased neuroserpin expression was seen in clusters of T cells in the paracortex of human lymph nodes, with some showing polarization to areas of cell:cell interaction. Our results support a role for neuroserpin and tissue plasminogen activator in activation-controlled proteolytic cleavage of proteins in the synaptic or perisynaptic space to modulate immune cell function.

Keywords: endothelial cells; lymph node; polarization; tissue plasminogen activator.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptive Immunity / physiology
  • Antigen Presentation
  • Cell Communication
  • Cell Polarity
  • Humans
  • Immunologic Memory
  • Immunological Synapses / physiology*
  • Lymph Nodes / cytology
  • Lymphocyte Activation / physiology*
  • Lymphocyte Function-Associated Antigen-1 / metabolism
  • Lymphocyte Subsets / metabolism
  • Membrane Glycoproteins / metabolism
  • Microscopy, Fluorescence
  • Monocytes / metabolism
  • Neuropeptides / genetics
  • Neuropeptides / metabolism*
  • Proteolysis
  • Receptors, Antigen, T-Cell / immunology
  • Secretory Vesicles / chemistry
  • Serpins / genetics
  • Serpins / metabolism*
  • Subcellular Fractions / chemistry
  • T-Lymphocytes / immunology*
  • T-Lymphocytes / metabolism
  • Tissue Plasminogen Activator / genetics
  • Tissue Plasminogen Activator / metabolism*
  • Up-Regulation

Substances

  • Lymphocyte Function-Associated Antigen-1
  • Membrane Glycoproteins
  • Neuropeptides
  • Receptors, Antigen, T-Cell
  • Serpins
  • TGOLN2 protein, human
  • neuroserpin
  • Tissue Plasminogen Activator