Inhibition of Primary Human T Cell Proliferation by Helicobacter pylori Vacuolating Toxin (VacA) Is Independent of VacA Effects on IL-2 Secretion

• Published in: Proceedings of the National Academy of Sciences - PNAS 2004-05, Vol.101 (20), p.7727-7732
• Main Authors: Sundrud, Mark S., Torres, Victor J., Unutmaz, Derya, Cover, Timothy L., Falkow, Stanley
• Format: Article
• Language: English
• Subjects: Bacterial Proteins - metabolism; Biological Sciences; CD4-Positive T-Lymphocytes - metabolism; Cell cycle; Cell Division - physiology; Cell growth; Cell lines; Chronic illnesses; Cyclosporins; Epithelial cells; Helicobacter pylori; Helicobacter pylori - metabolism; Humans; Immunology; Infections; Interleukin-2 - metabolism; Ion channels; Jurkat Cells; Microbiology; Secretion; T lymphocytes; Toxins
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0401528101

Recent evidence indicates that the secreted Helicobacter pylori vacuolating toxin (VacA) inhibits the activation of T cells. VacA blocks IL-2 secretion in transformed T cell lines by suppressing the activation of nuclear factor of activated T cells (NFAT). In this study, we investigated the effects of VacA on primary human CD4+T cells. VacA inhibited the proliferation of primary human T cells activated through the T cell receptor (TCR) and CD28. VacA-treated Jurkat T cells secreted markedly diminished levels of IL-2 compared with untreated cells, whereas VacA-treated primary human T cells continued to secrete high levels of IL-2. Further experiments indicated that the VacA-induced inhibition of primary human T cell proliferation was not attributable to VacA effects on NFAT activation or IL-2 secretion. We show here that VacA suppresses IL-2-induced cell-cycle progression and proliferation of primary human T cells without affecting IL-2-dependent survival. Through the analysis of a panel of mutant VacA proteins, we demonstrate that VacA-mediated inhibition of T cell proliferation requires an intact N-terminal hydrophobic region necessary for the formation of anion-selective membrane channels. Remarkably, we demonstrate that one of these mutant VacA proteins [VacA-Δ(6-27)] abrogates the immunosuppressive actions of wild-type VacA in a dominant-negative fashion. We suggest that VacA may inhibit the clonal expansion of T cells that have already been activated by H. pylori antigens, thereby allowing H. pylori to evade the adaptive immune response and establish chronic infection.