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Purpose This study addresses the sensitivity of different peripheral CD4+ T-lymphocyte subsets to irradiation (IR) and identifies potential targets for the prevention or treatment of radiation-induced toxicity. Methods This study was performed on peripheral blood mononuclear cells or sorted peripheral memory lymphocytes of CCR6+ mucosa-homing Th17/CCR6negTh and regulatory T subtypes of healthy volunteers. Cells were irradiated with a 2 Gy with or without pharmacologic inhibitors of different signaling pathways. Senescence of irradiated cells was assessed by resistance to apoptosis and determination of various senescence-associated biomarkers (senescence associated b-galactosidase activity, p16Ink4a-, p21Cdkn1a-, gH2A.X-, H2A.J expression). Cytokine production was measured in supernatants of irradiated cells by Luminex technology. Results Not all CD4+ memory T lymphocyte subsets were equally radiosensitive. High sensitivity of CCR6+Th17 lymphocytes to IR-induced senescence was shown by expression of the histone variant H2A.J, higher SA-b-Gal activity, and upregulation of p16Ink4a and p21Cdkn1a expression. Lower Annexin V staining and cleaved caspase-3, and higher expression of antiapoptotic genes Bcl-2 and Bcl-xL LF, showed that CCR6+Th17 lymphocytes were more resistant to IR-induced apoptosis than CCR6neg memory Th and regulatory T lymphocytes. After a 2 Gy IR, both CCR6+Th17 and CCR6neg cells acquired a moderate senescence-associated secretory phenotype, but only CCR6+Th17 cells secreted interleukin 8 (IL-8) and vascular endothelial growth factor-A (VEGF-A). Pharmacologic targeting of reactive oxygen species (ROS), mitogen-activated protein kinases (MAPKs), and mammalian target of rapamycin (mTOR) signaling pathways prevented the expression of senescent markers and IL-8 and VEGF-A expression by CCR6+Th17 cells after IR. Conclusions This study suggests that IR induces senescence of CCR6+Th17 lymphocytes associated with secretion of IL-8 and VEGF-A that may be detrimental to the irradiated tissue. ROS-MAPKs signaling pathways are candidate targets to prevent this CCR6+Th17-dependent radiation-induced potential toxicity. Finally, the ratio of circulating H2A.J+ senescent CCR6+ Th17/CD4+ T lymphocytes may be a candidate marker of individual intrinsic radiosensitivity.

Ionizing radiation-exposure induces a variety of cellular reactions, such as senescence and apoptosis. Senescence is a permanent arrest state of the cell division, which can be beneficial or detrimental for normal tissue via an inflammatory response and senescence-associated secretion phenotype. Damage to healthy cells and their microenvironment is considered as an important source of early and late complications with an increased risk of morbidity in patients after radiotherapy (RT). In addition, the benefit/risk ratio may depend on the radiation technique/dose used for cancer eradication and the irradiated volume of healthy tissues. For radiation-induced fibrosis risk, the knowledge of mechanisms and potential prevention has become a crucial point to determining radiation parameters and patients' intrinsic radiosensitivity. This review summarizes our understanding of ionizing radiation-induced senescent cell in fibrogenesis. This mechanism may provide new insights for therapeutic modalities for better risk/benefit ratios after RT in the new era of personalized treatments.

Chronic exposure to environmental pollutants is often associated with systemic inflammation. As such, cigarette smoking contributes to inflammation and lung diseases by inducing senescence of pulmonary cells such as pneumocytes, fibroblasts, and endothelial cells. Yet, how smoking worsens evolution of chronic inflammatory disorders associated with Th17 lymphocytes, such as rheumatoid arthritis, psoriasis, Crohn’s disease, and multiple sclerosis, is largely unknown. Results from human studies show an increase in inflammatory CD4+ Th17 lymphocytes at blood- and pulmonary level in smokers. The aim of the study was to evaluate the sensitivity of CD4+ Th17 lymphocytes to cigarette smoke-induced senescence. Mucosa-homing CCR6+ Th17- were compared to CCR6neg -and regulatory T peripheral lymphocytes after exposure to cigarette smoke extract (CSE). Senescence sensitivity of CSE-exposed cells was assessed by determination of various senescence biomarkers (β-galactosidase activity, p16Ink4a- and p21 expression) and cytokines production. CCR6+ Th17 cells showed a higher sensitivity to CSE-induced senescence compared to controls, which is associated to oxidative stress and higher VEGFα secretion. Pharmacological targeting of ROS- and ERK1/2 signalling pathways prevented CSE-induced senescence of CCR6+Th17 lymphocytes as well as VEGFα secretion. Altogether, these results identify mechanisms by which pro-oxidant environmental pollutants contribute to pro-angiogenic and pathogenic CCR6+Th17 cells, therefore potential targets for therapeutic purposes.

By revisiting CD90, a GPI-anchored glycoprotein, we show that CD90 is expressed by a subset of CD4+ and CD8+ human T cells. CD4+CD90+ cells share similarities with Th17 cells because they express the Th17-specific transcription factor RORC2 and produce IL-17A. CD4+CD90+ cells are activated memory T cells that express the gut mucosal markers CCR6, CD161, and the α4 and β7 integrins. Compared with CD90-depleted CCR6+ memory Th17 cells, CD4+CD90+ cells express higher levels of IL-22 and proinflammatory cytokines (IL-6, TNF-α and GM-CSF), but they produce lower levels of IL-21 and no IL-9. Analyses of CD8+CD90+ cells reveal that they express RORC2 and are able to produce higher levels of IL-17A, IL-22, and CCL20 compared with CD90-depleted CD8+ cells. These data show that CD90 identifies Th17 and Tc17 cells with a peculiar cytokine profile. Studies of circulating CD90+ cells in HIV patients show that CD90+ cells are decreased with an imbalance of the CD4+CD90+/regulatory T cell ratio in nontreated patients compared with treated patients and healthy donors. Overall, human CD90 identifies a subset of Th17 and Tc17 cells within CD4+ and CD8+ T cells, respectively, which are depleted during HIV infection.

We have analyzed the promoter of human gilz (glucocorticoid-induced leucine zipper), a dexamethasone-inducible gene that is involved in regulating apoptosis, and identified six glucocorticoid (GC)-responsive elements and three Forkhead responsive elements (FHREs). Promoter deletion analysis and point mutations showed that individual mutation of the GC-responsive elements does not affect GC-induced transcription and that FHRE-1 and FHRE-3 elements contribute to the effects of GCs. Furthermore, overexpression of the Forkhead transcription factor FoxO3 enhances GC-induced gilz mRNA expression. The functional significance of the interaction between FoxO3 and GC receptor was established in T lymphocytes. Indeed, we show that GCs failed to induce GILZ expression in the presence of IL-2, a cytokine known to antagonize GC effects in T cells. Using a constitutive active mutant of protein kinase B that inactivates FoxO3 or a FoxO3 mutant that cannot be inactivated by protein kinase B, we demonstrate that IL-2 inhibitory effects on GILZ expression are mediated through inhibition of FoxO3 transcriptional activity. Therefore, FoxO3 appears to be a key factor mediating GC and IL-2 antagonism for gilz regulation in T lymphocytes. This regulation of GILZ expression was placed in a meaningful context in evaluating the effects of GILZ on GC-induced apoptosis in T lymphocytes.