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Identification of Mediators of T-cell Receptor Signaling via the Screening of Chemical Inhibitor Libraries
08:49

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Published on: January 22, 2019

The Src family kinase Fyn mediates signals induced by TCR antagonists

Qizhi Tang1, Sumit K Subudhi, Kammi J Henriksen

  • 1The Diabetes Center, University of California, San Francisco, CA 94143, USA.

Journal of Immunology (Baltimore, Md. : 1950)
|April 24, 2002
PubMed

Insights

FcR nonbinding anti-CD3 epsilon monoclonal antibodies (mAbs) induce T cell tolerance by partially activating T cell receptor (TCR) signaling. This process involves Fyn kinase, which mediates partial signaling and T cell inactivation.

Area of Science:

  • Immunology
  • Cellular Biology
  • Molecular Signaling

Background:

  • FcR nonbinding anti-CD3 epsilon monoclonal antibodies (mAbs) induce T cell unresponsiveness and tolerance.
  • Understanding the membrane-proximal events is crucial for elucidating T cell inactivation mechanisms.

Purpose of the Study:

  • To investigate the membrane-proximal signaling events induced by FcR nonbinding anti-CD3 mAbs.
  • To identify the key molecular players involved in T cell inactivation mediated by these antibodies.

Main Methods:

  • Analysis of T cell receptor (TCR) complex aggregation and translocation.
  • Examination of tyrosine phosphorylation of signaling molecules like Cbl and linker for activation of T cells (LAT).
  • Overexpression studies of Fyn and Lck kinases in primary T cells.

Main Results:

  • FcR nonbinding anti-CD3 mAbs prevented TCR complex aggregation and translocation into membrane microdomains.
  • These mAbs induced tyrosine phosphorylation of Cbl, a Fyn substrate, but not LAT, a ZAP-70 substrate.
  • Overexpression of Fyn, but not Lck, restored T cell responsiveness to FcR nonbinding anti-CD3.

Conclusions:

  • Fyn kinase plays a critical role in mediating the partial TCR signaling induced by FcR nonbinding anti-CD3 mAbs.
  • These findings suggest a mechanism for T cell inactivation involving Fyn-dependent signaling pathways.
  • Targeting Fyn may offer therapeutic strategies for modulating T cell responses.

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