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Two isoforms of otubain 1 regulate T cell anergy via GRAIL

Luis Soares1, Christine Seroogy, Heidi Skrenta

  • 1Department of Medicine, Division of Immunology and Rheumatology, Stanford University School of Medicine, Stanford, California 94305, USA.

Nature Immunology
|December 9, 2003
PubMed

Insights

Two ubiquitin-specific protease isoforms of otubain 1 control T cell anergy by regulating GRAIL stability. One isoform promotes T cell proliferation, while the other induces anergy.

Area of Science:

  • Immunology
  • Molecular Biology
  • Cell Biology

Background:

  • The ubiquitin E3 ligase GRAIL is essential for inducing CD4 T cell anergy.
  • GRAIL's regulation is key to understanding T cell immune responses and tolerance.

Purpose of the Study:

  • To investigate the role of otubain 1 isoforms in regulating GRAIL and T cell anergy.
  • To elucidate the opposing functions of otubain 1 isoforms in T cell signaling.

Main Methods:

  • Utilized retroviral transduction in T cell receptor-transgenic mice.
  • Analyzed GRAIL protein levels, T cell proliferation, and interleukin 2 production.
  • Employed a mouse model with bone marrow reconstitution after lethal irradiation.

Main Results:

  • Otubain 1 expression led to low GRAIL levels, robust T cell proliferation, and high interleukin 2 production.
  • The otubain 1 alternative reading frame 1 isoform resulted in high GRAIL levels and functional T cell anergy.
  • Opposing functions of otubain 1 isoforms were demonstrated in controlling GRAIL stability and T cell phenotype.

Conclusions:

  • Otubain 1 isoforms differentially regulate GRAIL stability, impacting T cell anergy.
  • These findings reveal a novel mechanism controlling T cell immune tolerance.
  • Targeting otubain 1 may offer therapeutic strategies for immune-related disorders.

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