Journal
JOURNAL OF IMMUNOLOGY
Volume 178, Issue 3, Pages 1498-1504Publisher
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.178.3.1498
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Funding
- NIAID NIH HHS [R37 AI034867, R37 AI034867-14] Funding Source: Medline
- NIGMS NIH HHS [R01 GM064625, R01 GM064625-05A1, R01GM064625] Funding Source: Medline
- PHS HHS [R01A103486, R01A1034867] Funding Source: Medline
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The Ca2+ sensor synaptotagmin (Syt) VII regulates the exocytosis of conventional lysosomes in several cell types. In CTLs, the Ca2+-regulated exocytosis of lytic granules/secretory lysosomes is responsible for the perforin/granzyme-mediated lysis of target cells. To investigate the role of Syt VII in CTL effector function, the expression and function of Syt VII were examined in wild-type and Syt VII-deficient mice. In comparison with Syt VII+/+ controls, Syt VII-/- animals were impaired in their ability to clear an infection with the intracellular pathogen Listeria monocytogenes. When isolated CTLs were examined, we found that Syt VII is expressed upon CTL activation and localizes to granzyme A-containing lytic granules. Syt VII-deficient CTLs have no defects in proliferation and cytokine production, and their lytic granules contain normal amounts of perforin and granzyme A and polarize normally at the immunological synapse. However, despite normal conjugate formation with target cells, CTLs from Syt VII-/- mice exhibit reduced effector activity, when compared with controls. Treatment of Syt VII+/+ or Syt VII-/- CTLs with an inhibitor of the perforin-mediated lytic pathway resulted in comparable levels of cytotoxic activity, suggesting that Syt VII regulates perforin-mediated cytolytic CTL responses.
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