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

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What goes up must come down: A tripartite Dok-3/Grb2/SHIP1 inhibitory module limits BCR signaling

Michael Reth1,2,3, Michael R Gold4

  • 1BIOSS Centre for Biological Signaling Studies, Albert-Ludwigs-Universität Freiburg, Freiburg, Germany.

European Journal of Immunology
|November 5, 2016
PubMed

Insights

The B-cell antigen receptor (BCR) can both activate and inhibit immune responses. A newly identified module directly binds to activated BCRs, preventing excessive B cell activation and calcium mobilization.

Area of Science:

  • Immunology
  • Molecular Biology
  • Cell Signaling

Background:

  • Immune regulation relies on balancing activating and inhibitory signals.
  • B cells utilize the B-cell antigen receptor (BCR) for activation and other receptors like FcγRIIb, CD22, and CD19 for signaling modulation.
  • Inhibitory receptors typically recruit phosphatases to dampen BCR signaling.

Purpose of the Study:

  • To investigate the mechanism by which inhibitory signals are relayed to the BCR.
  • To identify components involved in negative feedback regulation of BCR signaling.
  • To understand how B cell activation is precisely controlled.

Main Methods:

  • Co-immunoprecipitation assays to identify protein interactions.
  • Biochemical assays to measure enzyme activity and signaling events.
  • Analysis of calcium mobilization in B lymphocytes.

Main Results:

  • A tripartite inhibitory module comprising Dok-3, Grb2, and SHIP1 directly binds to activated BCRs.
  • This module limits calcium (Ca2+) mobilization essential for B lymphocyte activation.
  • The BCR itself can initiate a negative feedback loop, acting as both an activator and inhibitor.

Conclusions:

  • The BCR possesses intrinsic inhibitory capabilities through direct recruitment of a negative regulatory module.
  • This mechanism provides a direct way to limit excessive BCR signaling and maintain immune homeostasis.
  • Findings challenge the notion that inhibitory receptors solely rely on recruiting phosphatases from a distance.

Keywords:
B cell receptor (BCR)Ca2+ mobilizationImmunoreceptor tyrosine-based activation motif (ITAM)Phosphoinositide 3-kinase (PI3K) signalingSH2 domain-containing inositol 5’-phosphatase (SHIP1)

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