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Extra-cellular superoxide promotes T cell expansion through inactivation of nitric oxide

Roel C van der Veen1, Therese A Dietlin, Armine Karapetian

  • 1Department of Neurology, University of Southern California Keck School of Medicine, MCH 142, 1333 San Pablo Street, Los Angeles, CA 90033, USA. vanderve@usc.edu

Journal of Neuroimmunology
|July 22, 2004
PubMed

Insights

Extracellular superoxide (EC-O2-) prevents nitric oxide (NO)-mediated immunosuppression of T cell proliferation. Inhibiting EC-O2- during T cell reactivation exacerbates experimental allergic encephalomyelitis (EAE) in mice lacking NADPH-oxidase (phox).

Area of Science:

  • Immunology
  • Cell Biology
  • Biochemistry

Background:

  • The precise mechanisms regulating nitric oxide (NO)-induced immunosuppression remain incompletely understood.
  • Extracellular superoxide (EC-O2-), produced by NADPH-oxidase (phox), is hypothesized to counteract NO-mediated suppression of T cell proliferation.
  • Mice deficient in p47(phox) exhibit resistance to experimental allergic encephalomyelitis (EAE), correlating with increased splenic NO activity, but a direct causal relationship has not been established.

Purpose of the Study:

  • To elucidate the role of extracellular superoxide (EC-O2-) in modulating nitric oxide (NO)-dependent immunosuppression during T cell activation.
  • To establish a causal link between NADPH-oxidase (phox) activity, EC-O2- production, and the severity of experimental allergic encephalomyelitis (EAE).

Main Methods:

  • Adoptive transfer of T cells into p47(phox-/-) mice under conditions of inhibited NO production.
  • Measurement of EC-O2- production during cognate T cell reactivation.
  • Assessment of NO activity following inhibition of EC-O2- using exogenous superoxide dismutase.
  • Evaluation of EAE severity in recipient mice.

Main Results:

  • Adoptive transfer of T cells into p47(phox-/-) mice resulted in severe EAE only when NO production during ex vivo donor cell reactivation was inhibited.
  • EC-O2- production was observed to increase during cognate T cell reactivation.
  • Inhibition of EC-O2- by exogenous superoxide dismutase led to enhanced NO activity.
  • These findings indicate that EC-O2- production promotes T cell expansion during peripheral immune response activation, rather than during established tissue inflammation.

Conclusions:

  • Extracellular superoxide (EC-O2-) plays a critical role in preventing nitric oxide (NO)-mediated immunosuppression of T cell proliferation.
  • NADPH-oxidase (phox)-derived EC-O2- regulates T cell expansion during the initial phases of immune response activation.
  • Targeting the interplay between EC-O2- and NO may offer novel therapeutic strategies for autoimmune diseases like EAE.

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