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Apoptotic pathways are selectively activated by granzyme A and/or granzyme B in CTL-mediated target cell lysis

Julián Pardo1, Alberto Bosque, Reina Brehm

  • 1Departmento de Bioquímica y Biología Molecular y Celular, Universidad de Zaragoza, E-50009 Zaragoza, Spain.

The Journal of Cell Biology
|November 10, 2004
PubMed

Insights

Perforin is crucial for granzyme-mediated apoptosis in target cells. Cytolytic T lymphocyte proteases granzyme A and B initiate distinct cell death pathways, highlighting perforin

Area of Science:

  • Immunology
  • Cell Biology
  • Molecular Biology

Background:

  • Cytolytic T lymphocyte (CTL) proteases granzyme A (gzmA) and granzyme B (gzmB) initiate distinct proapoptotic pathways.
  • The physiological relevance of these pathways in CTL-mediated target cell apoptosis remains unclear.

Purpose of the Study:

  • To investigate the roles of gzmA and gzmB in CTL-mediated apoptosis using perforin-deficient (perf) and granzyme-deficient mouse models.
  • To elucidate the specific contributions of gzmA and gzmB to early apoptotic events and caspase activation.

Main Methods:

  • Utilized ex vivo virus-immune CD8(+) T cells from mice deficient in perforin, gzmA, and/or gzmB.
  • Employed the Fas-resistant EL4.F15 tumor target cell line.
  • Assessed phosphatidyl serine (PS) exposure, mitochondrial membrane potential (Delta Psi(m)) loss, reactive oxygen radical generation, and caspase activation.

Main Results:

  • CTL from gzmA(-/-) or gzmB(-/-) mice induced early apoptotic features with distinct kinetics.
  • CTL from gzmA(-/-) mice activated caspase 3 and 9, unlike those from gzmB(-/-) mice.
  • Perforin was essential for all granzyme-induced apoptotic features, acting as the principal regulator.

Conclusions:

  • Perforin is the principal regulator of CTL-mediated and granzyme-facilitated intracellular processes.
  • The distinct apoptotic pathways initiated by gzmA and gzmB may represent a host strategy to overcome pathogen and tumor evasion tactics.

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