Investigating the kinetics of thymus recovery following acute damage and bone marrow transplantation

Abstract

Following ablative therapies used for different diseases such as cancer, damage to the thymus disrupts its ability to support T-cell development. Restoration of thymus function, either endogenously or after transplant, is critical in re-establishing the peripheral T cell compartment. Although the thymus has capability to repair following damage, the ability of the thymus to impose tolerance on newly developing thymocytes is poorly understood. Initially, Sub-Lethal Irradiation (SLI) was used as a model of thymic injury and endogenous thymus regeneration. Post SLI, it was found that the thymus recovers in two distinct phases where an early phase depends upon an intrathymic radioresistant progenitor. Furthermore, analysis of thymic microenvironments revealed that the cTEC compartment was maintained and able to support thymocyte development. However, the mTEC and intrathymic DC compartment were significantly impaired. Consequently, post SLI, Treg selection was reduced and the negative selection process was impaired as revealed by the development of ‘forbidden’ self-antigen specific thymocytes. Following BMT, cTEC numbers were also maintained while the mTEC and DC compartment sustained long term decline. While conventional CD4+ and CD8+ single positive thymocyte recovery was rapid, the kinetics of medulla-dependent Foxp3+ Treg was slower in comparison. Furthermore, analysis of negative selection through endogenously expressed self-antigens and active Caspase3 expression revealed that negative selection was impaired post BMT. Importantly, transfer of CD4+ thymocytes from BMT mice into nude hosts generated autoimmune symptoms including lymphocytic infiltrates and auto-antibodies. Collectively, these findings indicate that following thymus damage, the thymic microenvironment has differential recovery kinetics that impacts the quality of newly produced T cells, with defects in medullary recovery leading to a loss of immune tolerance and autoimmunity.