Regulation of thymus function and aging by the sympathetic nervous system

Project Summary/Abstract The thymus is the primary lymphoid organ for T cell development and education. During preadolescence, the thymus generates a critical lifelong T cell repertoire that establishes peripheral immune surveillance and central tolerance. However, the thymus undergoes age-dependent thymic involution, a natural and progressive deterio- ration of thymic structure and functionality, which permits the emergence of infectious and neoplastic diseases in the elderly. Intriguingly, detailed mechanistic underpinnings behind thymic decline with aging remain incom- pletely understood. Recognizing the importance of thymus health for longevity and quality of life, our work aims to explore innovative strategies to mitigate thymic involution. Our previous research has shed light on the signif- icant influence of the sympathetic nervous system on lymphoid organ (i.e., bone marrow) homeostasis. However, previous efforts in characterizing the microanatomy and function of SNS circuits within thymic compartments have yielded ambiguous results. Our approach to address these issues involves a two-pronged investigation. In the first aim, we will map the intrathymic trajectory of β-adrenergic innervation, the key SNS branch innervating the thymus. By integrating cutting-edge techniques like optical tissue clearing, confocal microscopy, and single- cell ATAC-sequencing, we will create a comprehensive spatial map of β-adrenergic nerve distribution relative to the thymic stromal network. Additionally, we will experimentally modulate β-adrenergic signaling to assess its impact on thymus structure and function. In the second aim, we will utilize methodological resources obtained from our first objective, including an in-depth digital pathology framework assessing intrathymic stromal topology, to investigate the role of β-adrenergic innervation in age-dependent thymic involution. By characterizing the de- teriorating effects of aging on thymic nerves and evaluating the consequences of β-adrenergic signal loss during aging, we seek to identify key signals responsible for thymic decline and dysfunction. Finally, we propose to examine the therapeutic potential of sympathomimetic pharmacotherapy (i.e., β-adrenergic agonists) in delaying and/or reversing thymic involution in aged mice, thus delivering the promise of pharmacologic interventions to preserve a functional immune system in the elderly. Overall, this research will illuminate the intricate interplay between the SNS and thymic parenchyma, potentially unlocking new strategies to combat immune system aging. By enhancing our understanding of the mechanisms underlying thymic involution, we aspire to improve immune competence and extend healthy lifespan in the aging population.