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Published on: August 13, 2013

Regulation of mature T lymphocyte proliferation and differentiation by Par-4

María José Lafuente1, Pilar Martin, Isabel Garcia-Cao

  • 1Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid, Canto Blanco, 28049 Madrid, Spain.

The EMBO Journal
|September 13, 2003
PubMed

Insights

The protein kinase C inhibitor Par-4 regulates T-cell immune responses. Loss of Par-4 enhances T-cell proliferation and promotes a Th2 immune response by affecting NF-kappaB and JNK signaling pathways.

Area of Science:

  • Immunology
  • Cell Biology
  • Molecular Biology

Background:

  • Par-4 (the atypical protein kinase C inhibitor) regulates NF-kappaB and JNK signaling pathways.
  • Genetic inactivation of Par-4 in fibroblasts increases NF-kappaB activation and decreases JNK stimulation.

Purpose of the Study:

  • To characterize the immunological phenotype of Par-4 knockout (Par-4(-/-)) mice.
  • To investigate the role of Par-4 in T-cell activation, proliferation, and differentiation.

Main Methods:

  • Analysis of peripheral T-cell responses in Par-4(-/-) mice upon T-cell receptor (TCR) stimulation.
  • Assessment of cell cycle entry, apoptosis, cytokine secretion (IL-2, IL-4), and cell surface marker expression (CD25).
  • Evaluation of NF-kappaB and JNK signaling pathway activation in T cells.

Main Results:

  • Par-4 deficiency leads to increased T-cell proliferation, cell cycle entry, and inhibited apoptosis.
  • Enhanced secretion of IL-2 and IL-4 in Par-4-deficient T cells.
  • Augmented TCR-triggered NF-kappaB activation and severely abrogated JNK activation.
  • NFATc1 activation was augmented in Par-4-deficient CD4+ T cells.

Conclusions:

  • Par-4 is a novel modulator of the immune response, particularly in T-cell activation and differentiation.
  • The absence of Par-4 promotes a Th2-skewed immune response.
  • Par-4 influences T-cell responses by impacting atypical protein kinase C (aPKC) activity, leading to altered JNK signaling.

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