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Identification of Mediators of T-cell Receptor Signaling via the Screening of Chemical Inhibitor Libraries
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Calcineurin imposes T cell unresponsiveness through targeted proteolysis of signaling proteins

Vigo Heissmeyer1, Fernando Macián, Sin-Hyeog Im

  • 1Center for Blood Research and Department of Pathology, Harvard Medical School, 200 Longwood Avenue, Boston, MA 02115, USA.

Nature Immunology
|February 20, 2004
PubMed

Insights

Calcium signaling triggers T cell anergy through protein degradation. This process involves ubiquitin ligases and impairs T cell receptor signaling and synapse stability.

Area of Science:

  • Immunology
  • Cellular Signaling
  • Molecular Biology

Background:

  • Sustained calcium signaling in T cells leads to anergy, a state of antigen unresponsiveness.
  • This anergy is primarily mediated by calcineurin and the nuclear factor of activated T-cells (NFAT).

Purpose of the Study:

  • To elucidate the molecular mechanisms underlying calcium-induced T cell anergy.
  • To investigate the role of protein degradation in the development of T cell anergy.

Main Methods:

  • Analysis of gene and protein expression of E3 ubiquitin ligases (Itch, Cbl-b, GRAIL) and ESCRT-1 components (Tsg101) in response to calcium signaling.
  • Assessment of protein degradation of PKC-theta and PLC-gamma1 via Western blotting.
  • Evaluation of T cell anergy induction in Itch- and Cbl-b-deficient mice.
  • Immunological synapse stability assays following T cell receptor (TCR) triggering.

Main Results:

  • Calcium signaling upregulated E3 ubiquitin ligases (Itch, Cbl-b, GRAIL) and Tsg101.
  • Itch and Nedd4 mediated the degradation of PKC-theta and PLC-gamma1, key signaling proteins.
  • T cells deficient in Itch and Cbl-b exhibited resistance to anergy induction.
  • Anergic T cells displayed impaired calcium mobilization and defective immunological synapse maintenance.

Conclusions:

  • Calcium-induced T cell anergy involves a multistep program of proteolytic protein degradation.
  • This program links calcineurin-driven gene transcription to impaired T cell signal transduction.
  • The findings reveal a novel mechanism regulating T cell responsiveness and immunological synapse stability.

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