Human CCR6+Th17 lymphocytes are highly sensitive to radiation-induced senescence and are a potential target for prevention of radiation-induced toxicity - Archive ouverte HAL Accéder directement au contenu
Article Dans Une Revue International Journal of Radiation Oncology, Biology, Physics Année : 2019

Human CCR6+Th17 lymphocytes are highly sensitive to radiation-induced senescence and are a potential target for prevention of radiation-induced toxicity

Patricia Zadigue
  • Fonction : Auteur
Alexandre De La Taille
  • Fonction : Auteur
Paul-Henri Romeo
  • Fonction : Auteur
Sabine Le Gouvello
  • Fonction : Auteur
Hoang Quy Nguyen
  • Fonction : Auteur
Yazid Belkacemi
  • Fonction : Auteur
Françoise Hoffschir
  • Fonction : Auteur
Stéphane Kerbrat
  • Fonction : Auteur
Mathieu Surénaud
  • Fonction : Auteur

Résumé

PURPOSE: To study the sensitivity of different peripheral CD4+ T-lymphocyte subsets to IR and identify potential targets for the prevention and/or treatment of radiation-induced toxicity. METHODS AND MATERIALS: This study was performed on peripheral blood mononuclear cells (PBMCs) or sorted peripheral memory lymphocytes of CCR6+ mucosa-homing Th17/CCR6negTh and regulatory T (Treg) subtypes of healthy volunteers. Cells were irradiated with a 2Gy +/- pharmacological inhibitors of different signaling pathways. Senescence of irradiated cells was assessed by resistance to apoptosis and determination of various senescence-associated biomarkers (senescence associated β-galactosidase (SA-β-Gal) activity, p16Ink4a-, p21Cdkn1a-, γH2A.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-β-Gal activity and upregulation of p16Ink4a and p21Cdkn1a expression. Lower Annexin V staining and cleaved caspase-3, and higher expression of anti-apoptotic genes Bcl-2 and Bcl-xL LF showed that CCR6+Th17 lymphocytes were more resistant to IR-induced apoptosis than CCR6neg memory Th and Treg lymphocytes. After a 2 Gy IR, both CCR6+Th17 and CCR6neg cells acquired a moderate senescence-associated secretory phenotype (SASP) but only CCR6+Th17 cells secreted IL-8 and VEGF-A. Pharmacological targeting of ROS, MAPKs, and mTOR signaling pathways prevented the expression of senescent markers and IL-8 and VEGF-A expression by CCR6+Th17 cells after IR. CONCLUSION: 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.
Fichier principal
Vignette du fichier
S0360301619339690.pdf (808.99 Ko) Télécharger le fichier
Origine : Fichiers produits par l'(les) auteur(s)

Dates et versions

hal-02359947 , version 1 (22-08-2022)

Licence

Paternité - Pas d'utilisation commerciale

Identifiants

Citer

Patricia Zadigue, Alexandre De La Taille, Paul-Henri Romeo, Sabine Le Gouvello, Hoang Quy Nguyen, et al.. Human CCR6+Th17 lymphocytes are highly sensitive to radiation-induced senescence and are a potential target for prevention of radiation-induced toxicity. International Journal of Radiation Oncology, Biology, Physics, 2019, ⟨10.1016/j.ijrobp.2019.10.045⟩. ⟨hal-02359947⟩
78 Consultations
128 Téléchargements

Altmetric

Partager

Gmail Facebook X LinkedIn More