Bacterial genotoxins induce T cell senescence.

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 T cells—the key mediators of adaptive immunity. We show that CDT induces premature senescence in activated CD4 T cells in vitro and provide evidence suggesting that infection with genotoxin-producing bacteria promotes T cell senescence in vivo. Moreover, we demonstrate that genotoxin-induced senescent CD4 T cells 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 T cell senescence. [Display omitted] • The bacterial genotoxin CDT induces senescence and a SASP in activated CD4 T cells • ATM plays a key role in orchestrating the SASP but not in the induction of senescence • ATM orchestrates the SASP via downstream activation of the p38 MAPK • Infection with genotoxigenic bacteria increases the proportion of GL13⁺ T cells in vivo Mathiasen et al. show that the bacterial genotoxin CDT induces senescence and a senescence-associated secretory phenotype (SASP) in T cells. The SASP is orchestrated by the ATM-p38 axis, whereas the induction of senescence is ATM independent. Together, the findings uncover a putative link between genotoxigenic bacteria, T cell senescence, and immunomodulation. [ABSTRACT FROM AUTHOR]