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* Section of Microbial Pathogenesis, Yale University School of Medicine, New Haven, CT 06510;
Department of Cell Biology, Yale University School of Medicine, New Haven, CT 06510; and
Section of Immunobiology, Yale University School of Medicine, New Haven, CT 06510
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.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by National Institutes of Health Grants RO1GM064625 and RO1A1034867 (to N.W.A.) and by a minority supplement to RO1A1034867 (to K.T.F.).
2 Current address: University of Colorado Health Sciences, Barbara Davis Center for Childhood Diabetes, Building M20, 1775 Ursula Street, Aurora, CO 80045-6511.
3 Current address: VaxInnate, New Haven, CT 06511.
4 Address correspondence and reprint requests to Dr. James W. Huleatt, VaxInnate, 300 George Street, New Haven, CT 06511. E-mail address: James.Huleatt{at}vaxinnate.com
5 Abbreviations used in this paper: [Ca2+]i, intracellular free Ca2+; BLT, benzyloxycarbonyl-L-lysine thiobenzyl ester; DAPI, 4',6'-diamidino-2-phenylindole; NRK, normal rat kidney; KO, knockout; MTS, 3-(4,5 dimethylthiazol-2yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium; pen/strep, penicillin/streptavidin; Syt, synaptotagmin; WT, wild type.
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