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Bacterial genotoxins induce T cell senescence

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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.

OriginalsprogEngelsk
Artikelnummer109220
TidsskriftCell Reports
Vol/bind35
Udgave nummer10
ISSN2211-1247
DOI
StatusUdgivet - 2021

Bibliografisk note

Funding Information:
We would like to thank Eleni Paparouna for the technical support in the in situ assays. This work was supported by a Postdoctoral grant and a Sapera Aude Talent grant from the Independent Research Fund Denmark (DFF-4092-00122 to T.K.); the Danish Cancer Society (R56-A2924-12-S2 to T.K. and R221-A13193 to L.G.-M.); the Lundbeck Foundation (2015-486 to M.G.); the Swedish Cancer Society (CAN 2017/315 to T.F.); the Swedish Research Council (2018-02521 to T.F.); the Kempestiftelserna (JCK-1826 to T.F.); the Cancer Research Foundation in Northern Sweden (AMP 17-884 to T.F.); Ume? University (to T.F.); the Novo Nordisk Research Foundation (NNF14OC0012345 to N.?.); and the LEO Foundation. The funders had no role in study design, data collection and analysis, the decision to publish, or preparation of the manuscript. Conceptualization, I.S.P. T.F. and T.K.; methodology and expertise, I.S.P. M.B.H. M.G. C.G. A.N.A. V.G.G. T.F. N.?. and T.K.; investigation, S.L.M. L.G.-M. I.S.P. S.D.P.T. M.R.J.N. O.C.B.M. C.K.V. K.N. D.B. and T.K.; resources, M.B.H. M.G. V.G.G. T.F. and N.?.; writing ? original draft, T.K.; writing ? review & editing, S.L.M. L.G.-M. I.S.P. S.D.P.T. M.R.J.N. M.B.H. O.C.B.M. C.K.V. K.N. D.B. M.G. C.G. A.N.A. V.G.G. T.F. and N.?.; visualization, I.S.P. S.D.P.T. T.F. and T.K.; supervision, I.S.P. T.F. and T.K.; funding acquisition, T.F. N.?. and T.K. All authors approved the manuscript. The authors declare no competing interests.

Funding Information:
We would like to thank Eleni Paparouna for the technical support in the in situ assays. This work was supported by a Postdoctoral grant and a Sapera Aude Talent grant from the Independent Research Fund Denmark ( DFF-4092-00122 to T.K.); the Danish Cancer Society ( R56-A2924-12-S2 to T.K. and R221-A13193 to L.G.-M.); the Lundbeck Foundation ( 2015-486 to M.G.); the Swedish Cancer Society ( CAN 2017/315 to T.F.); the Swedish Research Council ( 2018-02521 to T.F.); the Kempestiftelserna ( JCK-1826 to T.F.); the Cancer Research Foundation in Northern Sweden ( AMP 17-884 to T.F.); Umeå University (to T.F.); the Novo Nordisk Research Foundation ( NNF14OC0012345 to N.Ø.); and the LEO Foundation . The funders had no role in study design, data collection and analysis, the decision to publish, or preparation of the manuscript.

Publisher Copyright:
© 2021 The Authors

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