Helicobacter pylori induces cell cycle arrest of T-lymphocytes

Helicobacter pylori leads to a chronic and potentially fatal inflammation of the gastric mu-cosa. We investigated the interaction of H. pylori with human lymphocytes in order to identify possible mechanisms of immune evasion. T- and B-lymphocytes were isolated from H. pylori infected patients and uninfected controls and stimulated with anti-CD3/CD28 or IL–6. Prolif-eration of lymphocytes was abolished upon co-incubation with different H. pylori strains at 1–5 bacteria per cell or with protein extracts of culture supernatants. Inhibition of proliferation was independent of known virulence factors. Characterization of this novel factor by gel fil-tration revealed an activity eluting with an apparent molecular weight between 30 ad 70 kDa. While antigen-specific activation of T-cells (as shown by NFAT-activation, IFN-gamma pro-duction and CD25 or CD69 upregulation) was intact, cell cycle analysis revealed that S-phase entry of T-cells was completely inhibited by H. pylori. Consequently, T-cells arrested in G1 phase of the cell cycle. Western blot analysis revealed markedly reduced phosphoryla-tion of the retinoblastoma protein pRb, suggesting inhibition of G1 CDK activity. In line with this, activities of cyclin D3 and cyclin E were downregulated, and levels of the CDK inhibitor p27Kip1 were elevated. Mouse embryonic fibroblasts deficient in p27 showed a significant decrease in H. pylori induced inhibition of cell proliferation, suggesting a central role for p27 in mediating H. pylori induced G1 arrest. Immune evasion by induction of a p27–mediated G1 arrest in lymphocytes thereby may be of major significance for the chronic persistence of the bacteria in the human stomach.

Keywords: Helicobacter stomach cell cycle lymphocytes proliferation