A Secreted Low--Molecular-Weight Protein From Helicobacter pylori Induces Cell-Cycle Arrest of T Cells

Background & aims: Although Helicobacter pylori is recognized by the human immune system, the bacteria are not eliminated and lead to a chronic inflammation of the gastric mucosa. Methods: We investigated the interaction of H pylori with human lymphocytes. T and B lymphocytes were isolated from H pylori-infected patients and stimulated with anti-CD3/CD28 or interleukin-6. Results: Proliferation of lymphocytes was abolished on co-incubation with different H pylori strains (1-5 bacteria/cell) or with protein extracts of culture supernatants. Inhibition of proliferation was independent of known virulence factors. The factor is a protein or protein complex with an apparent molecular weight between 30 and 60 kilodaltons, clearly distinct from VacA. Although antigen-specific activation of T cells (as shown by nuclear factor of activated T cells [NFAT]-activation, interferon-γ production, and CD25 or CD69 up-regulation) remained intact, cell-cycle analysis showed that S-phase entry of T cells was inhibited completely by H pylori. Consequently, stimulated T cells arrested in the G1 phase of the cell cycle. Western blot analysis showed markedly reduced phosphorylation of the retinoblastoma protein (pRb), suggesting inhibition of G1 cyclin-dependent kinase activity. In line with this, activities of cyclin D3 and cyclin E were down-regulated, and levels of the cyclin-dependent kinase inhibitor p27Kip1 were increased. Mouse embryonic fibroblasts deficient in p27 showed a decrease in H pylori-induced inhibition of cell proliferation, suggesting a central role for p27 in mediating H pylori-induced G1 arrest. Conclusions: Induction of cell-cycle arrest in lymphocytes may be of major significance for the chronic persistence of bacteria in the human stomach.