Bacterial genotoxins induce T cell senescence

Mathiasen, Sarah L.; Gall-Mas, Laura; Pateras, Ioannis S.; Theodorou, Sofia D.P.; Namini, Martin R J; Hansen, Morten Bagge; Martin, Océane; Vadivel, Chella Krishna; Ntostoglou, Konstantinos; Butter, Deborah; Givskov, Michael; Geisler, Carsten; Akbar, Arne N.; Gorgoulis, Vassilis G.; Frisan, Teresa; Ødum, Niels; Krejsgaard, Thorbjørn

doi:10.1016/j.celrep.2021.109220

Cited by 28 publications

(33 citation statements)

References 73 publications

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“…Interestingly, CD4 + T lymphocytes from older individuals show diminished autophagy, accumulation of dysfunctional mitochondria, and increased ROS, leading to the phosphorylation of STAT-3 and consequently, to the production of Th17-related mediators that could trigger differentiation and activation of osteoclasts and inhibition of osteoblasts [ 87 ] ( Figure 6 ). Recently, it was reported that CDT genotoxin, a virulence factor present in pathogenic Gram-negative bacteria closely linked to periodontitis, is able to induce senescence in CD4 + T lymphocytes [ 83 ]. Moreover, DDR signaling can trigger the p38 MAPK activation and consequently, the production of a distinct SASP pattern in activated CD4 + T lymphocytes, including the production of Th17-type cytokines [ 83 ].…”

Section: P38 Mapk As a Driver Of Sasp Development In Senescent Cd4 ...mentioning

confidence: 99%

“…Recently, it was reported that CDT genotoxin, a virulence factor present in pathogenic Gram-negative bacteria closely linked to periodontitis, is able to induce senescence in CD4 + T lymphocytes [ 83 ]. Moreover, DDR signaling can trigger the p38 MAPK activation and consequently, the production of a distinct SASP pattern in activated CD4 + T lymphocytes, including the production of Th17-type cytokines [ 83 ]. However, it is unknown whether the activation of p38 MAPK in senescent CD4 + CD28 − T lymphocytes is responsible for the autophagic dysfunction that could eventually induce the production of a Th17-biased SASP; thus, more studies on this subject are necessary.…”

Section: P38 Mapk As a Driver Of Sasp Development In Senescent Cd4 ...mentioning

confidence: 99%

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Senescent CD4+CD28− T Lymphocytes as a Potential Driver of Th17/Treg Imbalance and Alveolar Bone Resorption during Periodontitis

González-Osuna

Sierra-Cristancho

Cafferata

et al. 2022

IJMS

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Senescent cells express a senescence-associated secretory phenotype (SASP) with a pro-inflammatory bias, which contributes to the chronicity of inflammation. During chronic inflammatory diseases, infiltrating CD4+ T lymphocytes can undergo cellular senescence and arrest the surface expression of CD28, have a response biased towards T-helper type-17 (Th17) of immunity, and show a remarkable ability to induce osteoclastogenesis. As a cellular counterpart, T regulatory lymphocytes (Tregs) can also undergo cellular senescence, and CD28- Tregs are able to express an SASP secretome, thus severely altering their immunosuppressive capacities. During periodontitis, the persistent microbial challenge and chronic inflammation favor the induction of cellular senescence. Therefore, senescence of Th17 and Treg lymphocytes could contribute to Th17/Treg imbalance and favor the tooth-supporting alveolar bone loss characteristic of the disease. In the present review, we describe the concept of cellular senescence; particularly, the one produced during chronic inflammation and persistent microbial antigen challenge. In addition, we detail the different markers used to identify senescent cells, proposing those specific to senescent T lymphocytes that can be used for periodontal research purposes. Finally, we discuss the existing literature that allows us to suggest the potential pathogenic role of senescent CD4+CD28- T lymphocytes in periodontitis.

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Section: P38 Mapk As a Driver Of Sasp Development In Senescent Cd4 ...mentioning

confidence: 99%

Section: P38 Mapk As a Driver Of Sasp Development In Senescent Cd4 ...mentioning

confidence: 99%

Senescent CD4+CD28− T Lymphocytes as a Potential Driver of Th17/Treg Imbalance and Alveolar Bone Resorption during Periodontitis

González-Osuna

Sierra-Cristancho

Cafferata

et al. 2022

IJMS

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“…It is noteworthy that STING can be activated in a cGAS-independent manner [48], and more globally that IRF3 and NF-κB can be activated by other routes during the DDR [49]. Thus, CDT-induced proinflammatory response might rely on other DDR factors like ATM, as demonstrated in T cells treated with typhoid toxin [50]. Besides, cGAS has also been shown to play a crucial role during cellular senescence induced by DNA damage [51].…”

Section: Discussionmentioning

confidence: 99%

Chronic exposure to Cytolethal Distending Toxin (CDT) promotes a cGAS-dependent type I interferon response

Pons

Pettes-Duler

Naylies

et al. 2021

Cell. Mol. Life Sci.

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The Cytolethal Distending Toxin (CDT) is a bacterial genotoxin produced by pathogenic bacteria causing major foodborne diseases worldwide. CDT activates the DNA Damage Response and modulates the host immune response, but the precise relationship between these outcomes has not been addressed so far. Here, we show that chronic exposure to CDT in HeLa cells or mouse embryonic fibroblasts promotes a strong type I interferon (IFN) response that depends on the cytoplasmic DNA sensor cyclic guanosine monophosphate (GMP)-adenosine monophosphate (AMP) synthase (cGAS) through the recognition of micronuclei. Indeed, despite active cell cycle checkpoints and in contrast to other DNA damaging agents, cells exposed to CDT reach mitosis where they accumulate massive DNA damage, resulting in chromosome fragmentation and micronucleus formation in daughter cells. These mitotic phenotypes are observed with CDT from various origins and in cancer or normal cell lines. Finally, we show that CDT exposure in immortalized normal colonic epithelial cells is associated to cGAS protein loss and low type I IFN response, implying that CDT immunomodulatory function may vary depending on tissue and cell type. Thus, our results establish a direct link between CDT-induced DNA damage, genetic instability and the cellular immune response that may be relevant in the context of natural infection associated to chronic inflammation or carcinogenesis.

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“…Activation of ATM simultaneously causes the phosphorylation of histone H2AX (gH2AX) as well as the recruitment of Mre11-Rad50-Nbs1 (MRN) complex, which provides a platform for DNA repair, and sets off checkpoint responses via the phosphorylation of CHK2 and p53, resulting in cell cycle arrest thus inhibiting cell proliferation (Figure 1) (72). In most cases, DNA damage becomes way too devastating, and the repair system fails to rescue the situation, which consequently leads to cell death (73,74) or senescence (75)(76)(77). However, in a few cases the intoxicated cells bypass death; these cells escape the built-in carcinogenesis barrier of cell death/senescence and are likely to develop a tendency for cancer formation, including genomic instability, heightened mutation frequency, and anchorage-independent cell growth (13,78,79).…”

Section: Bacterial Genotoxins and Their Biological Functionsmentioning

confidence: 99%

From DNA Damage to Cancer Progression: Potential Effects of Cytolethal Distending Toxin

Lai

Chang

et al. 2021

Front. Immunol.

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Cytolethal distending toxin (CDT), one of the most important genotoxins, is produced by several gram-negative bacteria and is involved in bacterial pathogenesis. Recent studies have shown that bacteria producing this peculiar genotoxin target host DNA, which potentially contributes to development of cancer. In this review, we highlighted the recent studies focusing on the idea that CDT leads to DNA damage, and the cells with inappropriately repaired DNA continue cycling, resulting in cancer development. Understanding the detailed mechanisms of genotoxins that cause DNA damage might be useful for targeting potential markers that drive cancer progression and help to discover new therapeutic strategies to prevent diseases caused by pathogens.

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Bacterial genotoxins induce T cell senescence

Cited by 28 publications

References 73 publications

Senescent CD4+CD28− T Lymphocytes as a Potential Driver of Th17/Treg Imbalance and Alveolar Bone Resorption during Periodontitis

Senescent CD4+CD28− T Lymphocytes as a Potential Driver of Th17/Treg Imbalance and Alveolar Bone Resorption during Periodontitis

Chronic exposure to Cytolethal Distending Toxin (CDT) promotes a cGAS-dependent type I interferon response

From DNA Damage to Cancer Progression: Potential Effects of Cytolethal Distending Toxin

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