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.