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* Department of Microbiology and Immunology, and
Department of Medicine Vanderbilt University School of Medicine, Nashville, TN 37232-2605, and
Veterans Affairs Tennessee Valley Healthcare System, Nashville, TN 37212
Helicobacter pylori are Gram-negative bacteria that persistently colonize the human gastric mucosa despite the recruitment of immune cells. The H. pylori vacuolating cytotoxin (VacA) recently has been shown to inhibit stimulation-induced proliferation of primary human CD4+ T cells. In this study, we investigated effects of VacA on the proliferation of various other types of primary human immune cells. Intoxication of PBMC with VacA inhibited the stimulation-induced proliferation of CD4+ T cells, CD8+ T cells, and B cells. VacA also inhibited the proliferation of purified primary human CD4+ T cells that were stimulated by dendritic cells. VacA inhibited both T cell-induced and PMA/anti-IgM-induced proliferation of purified B cells. Intoxication with VacA did not alter the magnitude of calcium flux that occurred upon stimulation of CD4+ T cells or B cells, indicating that VacA does not alter early signaling events required for activation and proliferation. VacA reduced the mitochondrial membrane potential of CD4+ T cells, but did not reduce the mitochondrial membrane potential of B cells. We propose that the immunomodulatory actions of VacA on T and B lymphocytes, the major effectors of the adaptive immune response, may contribute to the ability of H. pylori to establish a persistent infection in the human gastric mucosa.
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 Grants R01-AI49131 (to D.U.), R01-AI39657, R01-DK53623 from the National Institutes of Health, by the Medical Research Department of the Department of Veterans Affairs (to T.L.C.), and by a Vanderbilt University Medical Center Discovery grant/Center for AIDS Research development grant (to T.L.C. and D.U.). Immunology core services and FACS analysis were supported by National Institutes of Health Grant P30 AI 54999 from Vanderbilt-Meharry Center for AIDS Research.
2 V.J.T. and S.E.V. contributed equally to this work.
3 Current address: The Center for Biomedical Research Institute for Biomedical Research and Department of Pathology, Harvard Medical School, Boston, MA 02115.
4 Address correspondence and reprint requests to Dr. Timothy L. Cover, Division of Infectious Diseases, A2200 Medical Center North, Vanderbilt University School of Medicine, Nashville, TN 37232; E-mail address: timothy.L.cover{at}vanderbilt.edu or Dr. Derya Unutmaz at the current address: New York University School of Medicine, Joan and Joel Smilow Research Center, 522 First Avenue, Smilow 10th Floor, Room 1011, New York, NY 10016; E-mail address: Derya.Unutmaz{at}med.nyu.edu
5 Abbreviations used in this paper: VacA, vacuolating cytotoxin; DC, dendritic cell; SEB, staphylococcal enterotoxin B.
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