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Measuring Mitochondrial Function of Naïve and Effector CD8 T Cells
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Metalloproteases regulate T-cell proliferation and effector function via LAG-3.

Nianyu Li1, Yao Wang, Karen Forbes

  • 1Department of Immunology, St Jude Children's Research Hospital, Memphis, TN 38105, USA.

The EMBO Journal
|January 25, 2007
PubMed
Summary

Metalloprotease-mediated cleavage of Lymphocyte-activation gene 3 (LAG-3) is crucial for T-cell proliferation and function. ADAM10 and ADAM17 enzymes regulate this process, essential for appropriate immune responses.

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Area of Science:

  • Immunology
  • Molecular Biology
  • Cell Biology

Background:

  • T-cell proliferation and effector function require tight control for effective immune responses.
  • Lymphocyte-activation gene 3 (LAG-3) is a negative regulatory protein found on activated T cells.

Purpose of the Study:

  • To investigate the role of metalloprotease-mediated cleavage of LAG-3 in regulating T-cell activation.
  • To identify the specific metalloproteases involved in LAG-3 cleavage and their regulatory mechanisms.

Main Methods:

  • Analysis of LAG-3 cleavage by ADAM10 and ADAM17 in T cells.
  • Investigation of T-cell receptor (TCR) signaling pathways, including PKCtheta, in modulating metalloprotease activity.
  • Use of noncleavable LAG-3 mutants and ADAM10 knockdown in T-cell proliferation assays.

Main Results:

  • LAG-3 cleavage is mediated by ADAM10 and ADAM17, with their activities modulated by TCR signaling.
  • ADAM10 mediates constitutive LAG-3 cleavage, increasing 12-fold upon T-cell activation.
  • ADAM17-mediated LAG-3 shedding is induced by TCR signaling in a PKCtheta-dependent manner.
  • Noncleavable LAG-3 mutants impaired T-cell proliferation and cytokine production.
  • ADAM10 knockdown reduced T-cell proliferation.

Conclusions:

  • LAG-3 cleavage is essential for efficient T-cell proliferation and cytokine production.
  • Metalloprotease cleavage of LAG-3 represents a novel regulatory mechanism for T-cell expansion and function.