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DNA-PKcs controls calcineurin mediated IL-2 production in T lymphocytes

Ara Kim Wiese1, Marie Schluterman Burdine1,2, Richard H Turnage3

  • 1Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, United States of America.

Plos One
|July 28, 2017
PubMed

Insights

DNA-PKcs regulates T cell IL-2 production by influencing the calcineurin pathway. This finding expands understanding beyond V(D)J recombination, impacting severe combined immuno-deficiency research.

Area of Science:

  • Immunology
  • Molecular Biology
  • Biochemistry

Background:

  • Severe combined immuno-deficiency (SCID) in mammals is linked to DNA-dependent protein kinase catalytic subunit (DNA-PKcs) loss.
  • DNA-PKcs's role in SCID was previously attributed solely to its function in V(D)J recombination for lymphocyte development.

Purpose of the Study:

  • To investigate the role of DNA-PKcs in Interleukin-2 (IL-2) production.
  • To elucidate the signaling pathway through which DNA-PKcs regulates IL-2 production in T cells.

Main Methods:

  • Utilized shRNA and chemical inhibitors to reduce DNA-PKcs activity in activated T cells.
  • Assessed IL-2 production, calcineurin activity, and NFAT nuclear translocation.
  • Investigated the expression of Cabin1 and the role of CHK2 kinase.

Main Results:

  • Reduced DNA-PKcs activity significantly decreased IL-2 production in activated T cells.
  • This reduction was mediated by inhibition of calcineurin activity and blocked NFAT nuclear translocation.
  • DNA-PKcs regulates calcineurin by modulating Cabin1 expression via CHK2 activation.

Conclusions:

  • DNA-PKcs is a critical regulator of IL-2 production, independent of its role in V(D)J recombination.
  • The findings highlight a novel mechanism involving DNA-PKcs, CHK2, Cabin1, and calcineurin in T cell activation.
  • This discovery supports further research into small molecule inhibitors of DNA-PKcs for clinical applications.

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