Vasudev, A. | Search bioRxiv

bioRxiv2025

Coordinated changes in thymic stromal and hematopoietic cells that define the perinatal to juvenile transition

T cells in the perinatal thymus have distinct phenotypes and functions that may be instructed by age-specific features of the microenvironment. We evaluated molecular and cellular profiles of thymic stromal cells, including thymic epithelial cells (TECs), mesenchyme, endothelium, and hematopoietic antigen presenting cells (hAPCs), from birth through one-month of age in mice. Single-cell transcriptional profiling, flow cytometry, and immunohistochemistry revealed coordinated stromal changes accompanied by altered thymocyte differentiation at defined transitional ages during the shift from perinatal growth to juvenile homeostasis, which was mirrored in humans. These analyses link diminished IGF2 expression by mesenchymal cells with activation of the RB pathway in TECs at the transition. Moreover, a coordinated increase in type I interferon signaling in stroma across the transition is associated with altered antigen processing and presentation signatures in TECs and hAPCs. Collectively, these datasets provide a resource to interrogate thymic stroma across the perinatal to juvenile transition.

immunology↗

bioRxiv2022

An early decline in ETPs reflects reduced pre-thymic progenitors and altered signals from the thymus microenvironment

Age-related thymus involution results in decreased T-cell production, contributing to increased susceptibility to pathogens. Elucidating mechanisms underlying involution will inform strategies to restore thymopoiesis. The thymus is colonized by circulating bone marrow (BM)-derived thymus seeding progenitors (TSPs) that differentiate into early T-cell progenitors (ETPs). We find ETP cellularity declines as early as 3 months (3MO) in mice. This initial ETP reduction could reflect changes in pre-thymic progenitors and/or thymic stromal niches. We demonstrate that the number of functional TSP/ETP niches is not reduced with age. Instead, the number of pre-thymic BM and circulating lymphoid progenitors is substantially reduced by 3MO, although their intrinsic ability to seed and differentiate in the thymus is maintained. Additionally, Notch signaling in BM progenitors and ETPs declines by 3MO, indicating defective niche quality contributes to the reduction in ETPs. Together, these findings indicate that diminished BM lymphopoiesis and thymic stromal support contribute to the initial decline in ETPs, setting the stage for progressive thymus involution. Summary statementThe number of early T-cell progenitors declines by 3 months of age in mice. This decline reflects a sharp drop in circulating thymus seeding progenitors, fewer bone marrow lymphoid progenitors, and reduced Notch signaling in both bone marrow and thymus.

immunology↗