The Initial Age-Associated Decline in Early T-Cell Progenitors Reflects Fewer Pre-Thymic Progenitors and Altered Signals in the Bone Marrow and Thymus Microenvironments

Authors

Jayashree Srinivasan
Anusha Vasudev
Carolyn Shasha
Hilary J Selden
Encarnacion Perez
Bonnie LaFleur
Shripad A Sinari
Andreas Krueger
Ellen R Richie
Lauren I R Ehrlich

Publication Date

8-1-2023

Journal

Aging Cell

Abstract

Age-related thymus involution results in decreased T-cell production, contributing to increased susceptibility to pathogens and reduced vaccine responsiveness. Elucidating mechanisms underlying thymus involution will inform strategies to restore thymopoiesis with age. The thymus is colonized by circulating bone marrow (BM)-derived thymus seeding progenitors (TSPs) that differentiate into early T-cell progenitors (ETPs). We find that ETP cellularity declines as early as 3 months (3MO) of age in mice. This initial ETP reduction could reflect changes in thymic stromal niches and/or pre-thymic progenitors. Using a multicongenic progenitor transfer approach, we demonstrate that the number of functional TSP/ETP niches does not diminish with age. Instead, the number of pre-thymic lymphoid progenitors in the BM and blood is substantially reduced by 3MO, although their intrinsic ability to seed and differentiate in the thymus is maintained. Additionally, Notch signaling in BM lymphoid progenitors and in ETPs diminishes by 3MO, suggesting reduced niche quality in the BM and thymus contribute to the early decline in ETPs. Together, these findings indicate that diminished BM lymphopoiesis and thymic stromal support contribute to an initial reduction in ETPs in young adulthood, setting the stage for progressive age-associated thymus involution.

Keywords

Mice, Animals, T-Lymphocytes, Bone Marrow, Thymus Gland, Signal Transduction, Mice, Inbred C57BL, Cell Differentiation

Comments

Supplementary Materials

Data Availability Statement

PMID: 37221658