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A Swiss Army knife for CTLs.

Peter Friedl1, Bettina Weigelin2

  • 1Department of Cell Biology (283), Radboud Institute for Molecular Life Sciences, Radboudumc, Geert Grooteplein 28, 6525 GA Nijmegen, the Netherlands; David H. Koch Center for Applied Research of Genitourinary Cancers, Department of Genitourinary Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Cancer Genomics Centre Netherlands (CGC.nl), Department of Molecular Cancer Research, University Medical Center Utrecht, HP Stratenum 3.217, Universiteitsweg 100, 3584 CG Utrecht, the Netherlands.

Immunity
|December 20, 2014
PubMed
Summary

Granzyme B, released by leukocytes, cleaves intracellular targets for cell death. New research shows it also degrades basement membranes, aiding cytotoxic T cell entry into inflamed tissues.

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Area of Science:

  • Immunology
  • Cell Biology
  • Molecular Biology

Background:

  • Granzyme B is a key cytotoxic effector molecule released by cytotoxic lymphocytes.
  • Its primary known function involves cleaving intracellular substrates to induce target cell apoptosis.
  • The extracellular role of granzyme B in immune cell migration remained largely unexplored.

Purpose of the Study:

  • To investigate the role of granzyme B in the migration of cytotoxic T cells.
  • To determine if granzyme B has extracellular substrates relevant to immune cell extravasation.

Main Methods:

  • Biochemical assays to detect granzyme B activity on extracellular matrix proteins.
  • In vitro models of endothelial transmigration.
  • Analysis of basement membrane protein degradation.

Main Results:

  • Granzyme B directly cleaves key basement membrane proteins, including collagen IV and laminin.
  • This cleavage facilitates the diapedesis (migration) of cytotoxic T cells through the endothelial barrier.
  • The enzyme activity is crucial for T cell infiltration into inflamed tissues.

Conclusions:

  • Granzyme B possesses a novel extracellular function beyond intracellular cytotoxicity.
  • It acts as a matrix-degrading protease, promoting cytotoxic T cell infiltration.
  • This finding reveals a new mechanism for immune cell trafficking in inflammatory responses.