Helicobacter pylori (Hp) is the causative agent of a variety gastric diseases such as peptic ulcers and chronic gastritis and is implicated as a risk factor in gastric cancer. These diseases are mediated by Hp virulence factors including vacuolating cytotoxin (VacA), which inhibits major histocompatibility complex class II mediated antigen presentation through its effect on the invariant chain dependent pathway and can induce apoptosis in epithelial cells. VacA is assumed to play a pivotal role in establishing chronic Hp infections, potentially though an effect on T cells, but the biochemical pathways in this process have been unclear. In the August 22 Science, Bettina Gebert and colleagues at the Max von Pettenkofer-Institut show that VacA inhibits proliferation of T cells through the T-cell receptor/interleukin-2 (IL-2) signaling pathway (Science, 301:1099-1102, August 22, 2003).

Gebert et al. investigated Hp–T-cell interactions by infecting Jurkat T cells with a variety of wildtype and mutant Hp strains. These Hp-infected T cells were stimulated with growth promoters and showed a 40 to 60% reduction in proliferation compared with control strains, suggesting Hp infection was blocking this growth stimulation. Application of concentrated bacterial culture supernatant (CCS) from strains producing (CCS⁺) or not producing (CCS^-) VacA also blocked T-cell proliferation. Tests for T-cell apoptosis proved negative under the assay conditions, suggesting that VacA possesses T-cell antiproliferative activity. Gebert et al. noted that the secretion of IL-2 and the IL-2 receptor (IL-2R) was necessary for efficient lymphocyte proliferation. They observed that purified VacA reduced IL-2 secretion 60 to 80% and that CCS⁺ treatment caused IL-2Rα surface localization to be downregulated.

The authors also showed that VacA blocked IL-2 production at the transcriptional level. Several transcription factors are essential for the activation of the IL-2 promoter, and they determined that only NFAT (which localizes to the nucleus following dephosphorylation by calcineurin) was strongly silenced after Hp treatment. NFAT translocation was blocked in 80% of the cells treated with Hp, and a constitutively active form of calcineurin was able to block this VacA effect, suggesting VacA acted at, or upstream of, calcineurin. In addition, the authors showed, via microarray analysis, that the medically important immunosuppressive drug FK506 (which is known to inhibit calcineurin) and VacA regulated a common set of genes, suggesting "a common mechanism of gene regulation by blocking calcineurin."

"The approach of using bacterial pathogens or viruses to block T lymphocyte activation and/or proliferation and to induce immune suppression has recently been recognized as a successful strategy in the interaction of microbes with its host," conclude the authors. Hp appears to be no different, as the secretion of VacA appears to be a "long distance weapon" to prevent T-cell proliferation and enhance Hp infectivity.