The thymus is the primary organ for the generation of a diverse repertoire of T cells essential for adaptive immunity. Despite its importance, the thymus undergoes atrophy or involution in adulthood or under pathological conditions such as irradiation, chemotherapy, systemic inflammation, and infection. The involution-associated decrease in T cell production and shrinkage of the T cell repertoire may contribute to the decline in immune functions and the increased infection-induced mortality and morbidity in the elderly. Delaying the course of thymic involution and improving thymic regeneration has been hindered by a poor understanding of the mechanistic control of thymic involution. Among the many cell lineages that compose the thymus, thymic epithelial cells (TECs) are particularly critical for maintaining thymus size and ensuring its function as a power-house of T cell production. Defects in TEC development, maintenance, or function can result in thymic involution and T cell deficiency, yet the precise mechanistic regulation of TECs necessary to maintain proper function remains unclear. We and others have demonstrated important roles for mTOR and its precise regulation by TSC1/2 in T cells and other immune cells. Two recent studies from our laboratory show that mTOR plays crucial roles in TEC differentiation and thymopoiesis via signaling through both mTORC1 and mTORC2. Specifically, mTORC1- deficiency in TECs causes severe thymic atrophy, altered thymic structure, impaired TEC maturation, and marked impairment of the generation of virtually all T cell lineages. Furthermore, the temporal control of the fetal-specific generation of IL-17-producing ??T17 cells and V?5+/V?6+-V?1+ ??T cells is lost in the absence of mTORC1, leading to the abnormal generation of these cells in adult mice. TEC-specific deficiency of mTORC2 also causes thymic atrophy and impaired T cell development, albeit to a lesser extent than mTORC1 deficiency and without impacting the temporal control of ??T cell development. Based on these observations, we hypothesize that postnatal TEC-specific mTOR signaling, mediated via multiple ligands, receptors, and downstream molecules, is required to regulate TEC function, maintenance, and heterogeneity, T cell development, thymic involution, and thymic rejuvenation. We will test our hypothesis by pursuing the following three specific aims: (1) to investigate the mechanisms by which TEC-specific mTOR contributes to thymic function; (2) to define the role of mTORC1 and mTORC2 in the maintenance and function of developed TECs, the prevention of thymic involution, and in thymic rejuvenation; and (3) to determine the impact of mTORC1 signaling in TECs on age-dependent regulation of thymic environment and ??T cell development..
The thymus is the primary organ that produces T cells, and its involution is associated with the impairment of T cell function in aged populations and in many pathological conditions. The proposed study is expected to improve understanding of the mechanisms that control thymic epithelial cell development and function and thymic atrophy. Such knowledge should guide the establishment of novel strategies to enhance thymic function and boost immunity in the elderly and in patients that require robust generation/maintenance of adaptive immunity.
