Negative selection of T cells by Helicobacter pylori as a model for bacterial strain selection by immune evasion

The majority of humans infected with Helicobacter pylori maintain a lifelon g infection with strains bearing the cag pathogenicity island (PAI). H. pyl ori inhibits T cell responses and evades immunity so the mechanism by which infection impairs responsiveness was investigated. Lt. pylori caused apopt otic T cell death, whereas Campylobacter jejuni did not. The induction of a poptosis by H. pylori was blocked by an anti-Fas Ab (ZB4) or a caspase 8 in hibitor. In addition, a T cell line with the Fas rendered nonfunctional by a frame shift mutation was resistant to H. pylori-induced death. H. pylori strains bearing the cag PAI preferentially induced the expression of Fas li gand (FasL) on T cells and T cell death, whereas isogenic mutants lacking t hese genes did not. Inhibiting protein synthesis blocked FasL expression an d apoptosis of T cells. Preventing the cleavage of FasL with a metalloprote inase inhibitor increased H. pylori-mediated killing. Thus, H. pylori induc ed apoptosis in Fas-bearing T cells through the induction of FasL expressio n. Moreover, this effect was linked to bacterial products encoded by the ca g PAI, suggesting that persistent infection with this strain may be favored through the negative selection of T cells encountering specific H. pylori Ags.