The role of paracrine growth factor signaling in thymus function and age-associated dysfunction

The thymus is the primary site of T lymphocyte development, where mutually inductive signaling between lymphoid progenitors and thymic epithelial cells (TECs) directs the progenitors along a well-characterized program of differentiation. However, the thymus atrophies with age, resulting in waning T cell immunity. Regeneration of the aged thymus can be achieved experimentally, but the underlying mechanisms are not well understood. Therefore durable, clinically relevant approaches for thymic regeneration have not yet been identified. Prior work has established that cortical TECs (cTECs) are the primary targets of atrophy and regeneration, but many aspects of their basic biology have been difficult to resolve because they represent a small fraction of thymus cellularity, and because their isolation requires enzymatic digestion that induces broad physiological changes. We recently found that cTECs have a unique labyrinth-like morphology, which is dynamically regulated during thymus atrophy and regeneration. Emerging evidence suggests that paracrine FGF21 signals mediated by mTOR are critical regulators of cTEC size, morphology, and metabolic processes, particularly autophagy, which is required for self-antigen presentation and T cell selection. FGF21, mTOR, and autophagy can each by manipulated by available therapeutics, with potential to regenerate the atrophied thymus. The proposed study aims to combine existing genetic models and advanced imaging analysis to independently manipulate FGF21, mTOR and autophagy pathways and identify their regulatory relationships and roles in controlling cTECs size and morphology, as well as their effects on overall thymus size and function. These studies will inform the design of an optimal combination therapeutic strategy for thymus regeneration in aged animals, which will be evaluated for its capacity to improve T cell responses to viral challenge.