Bacterial genotoxins induce Tcell senescence.

Abstract

Several types of pathogenic bacteria produce genotoxins that induce DNA damage in host cells. Accumulating evidence suggests that a central function of these genotoxins is to dysregulate the host's immune response, but the underlying mechanisms remain unclear. To address this issue, we investigated the effects of the most widely expressed bacterial genotoxin, the cytolethal distending toxin (CDT), on Tcells-the key mediators of adaptive immunity. We show that CDT induces premature senescence in activated CD4 Tcells invitro and provide evidence suggesting that infection with genotoxin-producing bacteria promotes Tcell senescence invivo. Moreover, we demonstrate that genotoxin-induced senescent CD4 Tcells assume a senescence-associated secretory phenotype (SASP) which, at least partly, is orchestrated by the ATM-p38 signaling axis. These findings provide insight into the immunomodulatory properties of bacterial genotoxins and uncover a putative link between bacterial infections and Tcell senescence.