Molecular mechanisms of thymic tolerance induction and recovery from involution

Abstract

Thymic epithelial cells (TECs) are vital for the formation of the thymic microenvironment and the differentiation of T cells. This process involves a series of interactions between TECs and thymocytes that govern T cell commitment, progenitor T cell proliferation and differentiation and TCR specificity-based selection of immature T cells to finally allow the release of mature T cells capable of mounting an immune response against foreign antigens (e.g. from pathogens), whilst remaining tolerant of self. Although the role of TECs in mediating these processes is well established, major gaps in our understanding of the molecular mechanisms involved in TEC development, maintenance and function remain. In this thesis we seek to address this knowledge gap and define: (a) the molecular mechanisms underlying TEC survival and death during injury; and (b) the molecular mechanisms that control the expression of peripheral tissue self-antigens (PTAs) in TEC which is required to mediate self-tolerance.

Atrophy of the thymus following irradiation or high-dose chemotherapy impairs immune recovery in patients, which is a significant cause of morbidity and mortality. Despite the importance of TECs for immunity, there is little understanding of the mechanisms that control TEC survival and death in the context of treatments that damage the immune system. By using different genetically modified mouse models targeting the intrinsic pathway of apoptosis in both TECs and thymocytes, we found that: (a) TECs die via the intrinsic apoptotic pathway after irradiation; (b) the pro-survival proteins BCL-2 and BCL-XL are crucial for TEC regeneration; and (c) blocking thymocyte death can partially rescue TECs following irradiation. These data provide new insights into the molecular control of TEC survival and regeneration that could be used to inform new treatments that maintain or restore thymic function in immunosuppressed patients.

A unique property of TECs is their capacity to express thousands of PTAs to mediate immune tolerance of non-lymphoid self-antigens. The autoimmune regulator, AIRE, is required for the transcription of the majority of these PTAs, and defects in AIRE’s function lead to autoimmune disease in mice and humans. The precise molecular mechanisms by which AIRE orchestrates such broad, tolerogenic transcription of PTAs in TECs remain only partially understood. We here show that the acetyltransferase, KAT7, which mediates the majority of histone 3 lysine 14 acetylation (H3K14ac), is essential for AIRE-mediated expression of PTAs, the establishment of a normal thymic microenvironment and self-tolerance. This study reveals an important role for histone acetylation in AIRE’s function in TEC and immunological tolerance.

In conclusion, these studies highlight essential molecular mechanisms underlying TEC survival, regeneration and function that are crucial for immune function and tolerance. This newly gained knowledge will further aid the design of treatment strategies for immune recovery after cytoablative and cancer treatment as well as autoimmune diseases.