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Signaling alterations in activation-induced nonresponsive CD8 T cells.

E L Tham1, M F Mescher

  • 1Center for Immunology, Department of Biochemistry, University of Minnesota, Minneapolis, MN 55455, USA.

Journal of Immunology (Baltimore, Md. : 1950)
|August 8, 2001
PubMed
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Activated CD8 T cells can become unresponsive to IL-2 production, a state called activation-induced non-responsiveness (AINR). This defect involves signaling pathways like ERK and p38, crucial for IL-2 gene expression and cell proliferation.

Area of Science:

  • Immunology
  • Cellular Biology
  • Molecular Signaling

Background:

  • Activated CD8 T cells initially expand via IL-2, but transiently, becoming anergic.
  • Activation-induced non-responsiveness (AINR) prevents IL-2 production despite full T cell receptor (TCR) stimulation.
  • AINR affects IL-2 production but not cytolytic function or IFN-gamma release.

Purpose of the Study:

  • To investigate the molecular mechanisms underlying IL-2 production defects in CD8 T cells experiencing AINR.
  • To identify specific signaling pathway dysregulations contributing to AINR in CD8 T cells.

Main Methods:

  • Utilized microspheres with defined stimuli (anti-TCR, peptide-MHC, B7-1, ICAM-1) to compare normal and AINR CD8 T cells.
  • Analyzed signaling pathway activation, including extracellular signal-regulated kinase (ERK), Janus kinase, and p38.

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  • Employed pharmacological inhibitors (PD98059, SB202190) and activators (PMA, ionomycin) to probe signaling defects.

    • Main Results:

    • AINR CD8 T cells showed transient ERK upregulation, reduced Janus kinase activation, and absent p38 activation.
    • Exogenous IL-2 restored proliferation in AINR cells, indicating a signaling defect upstream of Ras and protein kinase C.
    • ERK and p38 kinase activation are essential for IL-2 production, with defects observed in AINR cells.

    Conclusions:

    • AINR in CD8 T cells is characterized by defective signaling through mitogen-activated protein kinases (MAPKs) like ERK and p38, and Janus kinase.
    • Restoration of ERK and p38 activation is critical for IL-2 production and proliferation in CD8 T cells.
    • Understanding these signaling defects provides insight into T cell anergy and potential therapeutic targets.