Sublethal Total Body Irradiation Causes Long-Term Deficits in Thymus Function by Reducing Lymphoid Progenitors

• Published in: The Journal of immunology (1950) 2017-10, Vol.199 (8), p.2701-2712
• Main Authors: Xiao, Shiyun, Shterev, Ivo D, Zhang, Wen, Young, Lauren, Shieh, Jae-Hung, Moore, Malcolm, van den Brink, Marcel, Sempowski, Gregory D, Manley, Nancy R
• Format: Article
• Language: English
• Subjects: Aging; Animals; Bone marrow; Bone Marrow Cells - physiology; Cell Differentiation; Cell Lineage; Cells, Cultured; Epithelial cells; Female; Females; Hematopoiesis - radiation effects; Hematopoietic stem cells; Immunologic Deficiency Syndromes - etiology; Immunologic Deficiency Syndromes - immunology; Irradiation; Long-term effects; Lymphocytes T; Lymphoid Progenitor Cells - physiology; Male; Males; Mice; Mice, Inbred C57BL; Proto-Oncogene Proteins c-kit - metabolism; Radiation; Rodents; Stem cell transplantation; Stem cells; Synchronization; T-Lymphocytes - physiology; Thymic involution; Thymopoiesis; Thymus; Thymus Gland - immunology; Thymus Gland - radiation effects; Transcription; Whole-Body Irradiation - adverse effects
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.1600934

Total body irradiation (TBI) damages hematopoietic cells in the bone marrow and thymus; however, the long-term effects of irradiation with aging remain unclear. In this study, we found that the impact of radiation on thymopoiesis in mice varied by sex and dose but, overall, thymopoiesis remained suppressed for ≥12 mo after a single exposure. Male and female mice showed a long-term dose-dependent reduction in thymic cKit lymphoid progenitors that was maintained throughout life. Damage to hematopoietic stem cells (HSCs) in the bone marrow was dose dependent, with as little as 0.5 Gy causing a significant long-term reduction. In addition, the potential for T lineage commitment was radiation sensitive with aging. Overall, the impact of irradiation on the hematopoietic lineage was more severe in females. In contrast, the rate of decline in thymic epithelial cell numbers with age was radiation-sensitive only in males, and other characteristics including transcription were unaffected. Taken together, these data suggest that long-term suppression of thymopoiesis after sublethal irradiation was primarily due to fewer progenitors in the BM combined with reduced potential for T lineage commitment. A single irradiation dose also caused synchronization of thymopoiesis, with a periodic thymocyte differentiation profile persisting for at least 12 mo postirradiation. This study suggests that the number and capability of HSCs for T cell production can be dramatically and permanently damaged after a single relatively low TBI dose, accelerating aging-associated thymic involution. Our findings may impact evaluation and therapeutic intervention of human TBI events.