Thymic epithelial cells (TECs) create a unique microenvironment that induces T cell commitment, guides their differentiation and imposes immune tolerance. Atrophy of the thymus following chemotherapy or irradiation impairs immune recovery in cancer patients, which is a significant cause of morbidity and mortality. These problems are particularly pronounced in adults due to the additional age-related involution of the thymus. Despite the importance of TECs for immunity, there is little understanding of the mechanisms that control TEC survival and death, especially in the context of cytoablative treatments that are known to damage the immune system. The aim of this project is to elucidate: (1) the mechanisms of TEC death in response to different cytoablative therapies, and; (2) which pro-survival BCL-2 family proteins are necessary for TEC survival and thymus regeneration.
To assess whether TEC death is induced by γ-irradiation directly or secondary due to the loss of thymocytes, the intrinsic apoptotic pathway was genetically blocked by deleting Bax and Bak in TECs only (using Foxn1Cre;Baxfl/fl;Bak-/- mice) or in thymocytes only (using CD4Cre;Baxfl/fl;Bak-/- mice). We found that γ-irradiation-induced TEC loss was rescued in CD4Cre;Baxfl/fl;Bak-/- mice. This demonstrates that TEC death is caused by the loss of thymocytes.
Our recent studies have shown that BCL-2 and BCL-XL are not critical for TEC homeostasis under steady-state conditions. However, we report here that γ-irradiation induces severe TEC damage in Foxn1Cre;Bcl2fl/fl and Foxn1Cre;Bclxfl/fl mice that cripples thymic recovery. These data point towards a differential role for these proteins in TEC survival under steady-state homeostasis versus recovery from injury.
Collectively, these findings reveal the molecular mechanisms that govern thymic epithelial cell survival and recovery following cytoablative therapies. This will enable the design of better approaches to protect and restore thymic function in cancer patients that are undergoing treatment with immunoablative agents.