The transcription factor NFAT exhibits signal memory during serial T cell interactions with antigen-presenting cells

Immunity. 2013 Feb 21;38(2):237-49. doi: 10.1016/j.immuni.2012.09.012. Epub 2013 Jan 11.

Abstract

Interactions with antigen-presenting cells (APCs) interrupt T cell migration through tissues and trigger signaling pathways that converge on the activation of transcriptional regulators, including nuclear factor of activated T cells (NFAT), which control T cell function and differentiation. Both stable and unstable modes of cognate T cell-APC interactions have been observed in vivo, but the functional significance of unstable, serial contacts has remained unclear. Here we used multiphoton intravital microscopy in lymph nodes and tumors to show that while NFAT nuclear import was fast (t(1/2 max)∼1 min), nuclear export was slow (t(1/2)∼20 min) in T cells. During delayed export, nuclear NFAT constituted a short-term imprint of transient TCR signals and remained transcriptionally active for the T cell tolerance gene Egr2, but not for the effector gene Ifng, which required continuous TCR triggering for expression. This provides a potential mechanistic basis for the observation that a predominance of unstable APC interactions correlates with the induction of T cell tolerance.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigen-Presenting Cells / immunology
  • Antigen-Presenting Cells / metabolism*
  • Antigen-Presenting Cells / pathology
  • Cell Communication
  • Cell Differentiation
  • Cell Movement
  • Cell Nucleus / metabolism
  • Cytosol / metabolism
  • Early Growth Response Protein 2 / genetics
  • Early Growth Response Protein 2 / immunology
  • Gene Expression Regulation
  • Humans
  • Immune Tolerance*
  • Immunologic Memory*
  • Interferon-gamma / genetics
  • Interferon-gamma / immunology
  • Lymph Nodes / immunology
  • Lymph Nodes / metabolism*
  • Lymph Nodes / pathology
  • Mice
  • Microscopy, Fluorescence, Multiphoton
  • NFATC Transcription Factors / genetics*
  • NFATC Transcription Factors / immunology
  • Protein Transport
  • Receptors, Antigen, T-Cell
  • Signal Transduction
  • T-Lymphocytes / immunology
  • T-Lymphocytes / metabolism*
  • Tumor Cells, Cultured

Substances

  • Early Growth Response Protein 2
  • Egr2 protein, mouse
  • NFATC Transcription Factors
  • Receptors, Antigen, T-Cell
  • Interferon-gamma