Understanding the mechanisms driving emergence of atypical age-associated thymic epithelial cells

The goal of this proposal is to define the cellular sources of atypical age associated thymic epithelial cells (aaTECs) and uncover molecular pathways that promote their emergence with aging. The thymus is a critical primary immune organ responsible for giving rise to a diverse, yet self-tolerant, T cell pool. This critical T cell development process is holistically governed by a group of thymic epithelial cells (TECs) that express the master transcription factor Foxn1. There are two major groups of TECs that are functionally and regionally distinguishable. Cortical TECs are responsible for the early stages of T cell development, while medullary TECs can express peripheral antigens and are tasked to delete autoreactive T cells. A strong population of effective thymic epithelial cells is critical for optimal thymic function and proper T cell immunity. With aging, both major TEC cell types operatively decline through a phenomenon called thymic involution. Here, the organ atrophies throughout lifespan and functional thymic epithelial cells are diminished. Despite thymic involution being well documented, the key mechanisms within the thymic stromal compartment that influences this phenomenon are incompletely understood. Our lab’s preliminary data describes that nonfunctional atypical aaTECs emerge and limits thymic function in aged mice. These aaTECs do not retain the classic thymic epithelial cell markers that are present within canonical TECs. Specifically, we have characterized novel markers for two aaTEC populations: aaTEC1 (marked as UEA1 neg, Ly51 neg, Claudin3 pos) and aaTEC2 (EpCAM neg, PDGRFa neg, and Podoplanin pos). Early tracing experiments indicate that aberrant age associated TECs come from bonafide thymic epithelial cells that have expressed Foxn1. Bioinformatic interactome analyses suggests that protein and cellular interactions are skewed away from conventional TECs, in favor of aaTECs. Furthermore, atypical aaTECs can respond to critical growth factors and co-opt these proteins away from classical TECs, likely contributing to their eventual decline. Lastly, we find that aaTECs appear to downregulate Foxn1 expression and highly express androgen and estrogen receptors, suggesting that these two pathways are relevant to their emergence with aging. Our initial characterization of aberrant aaTECs notwithstanding, the stromal cells that transition to aaTECs and vital molecular cues that promote them have not been fully explored. Therefore, with our exciting findings, the goal of my proposal is to know the key thymic epithelial cells that serve as pre-cursors to aaTECs (Aim 1) and discover major pathways that induce aaTEC formation with aging (Aim 2). Through the F31 fellowship, I will not only continue to enhance my skills as a PhD student, but my findings will also contribute to efforts in creating therapeutics to boost thymic function within aging populations. This prestigious fellowship will also provide me with the necessary training and support system to further my goal in becoming an independent researcher and leading my own scientific enterprise. Project Number: 1F31AG094107-01 | Fiscal Year: 2025 | NIH Institute/Center: National Institute on Aging (NIA) | Principal Investigator: Dante Dennis Acenas II | Institution: UNIVERSITY OF WASHINGTON, SEATTLE, WA | Award Amount: $49,538 | Activity Code: F31 | Study Section: Special Emphasis Panel[ZRG1 F07B-G (20)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11160287