Spatial remodeling of the thymic stroma with age disrupts niches for T cell selection and tolerance

Tarcevski, A., Dhalla, F., Moore, J., Zuklys, S., Kusch, A., Tchernev, L., Grier, J., Maio, S., Khan, A., Barthlott, T., Deadman, M., Handel, A. E., Byrne, H., Hollander, G.

University of Oxford · biorxiv

Paper

Abstract

Age-associated thymic involution is a major driver of immunosenescence, yet the cellular and spatial mechanisms coordinating age-related thymic remodeling remain incompletely understood. Combining single-cell transcriptomics, chromatin accessibility profiling, and spatial transcriptomics, we generated a spatially resolved multi-omic atlas of the aging mouse thymus. We show that thymic aging is not simply a process of epithelial loss, but a spatial reorganization of the stroma into new microenvironments, including age-associated epithelial states, a fibroblast-supported epithelial progenitor niche, and tertiary lymphoid structures. This remodeling displaces niches supporting positive and negative thymocyte selection and coincides with an intrinsic decline in cortical thymic epithelial cell function. Ligand-receptor mapping identifies medullary fibroblasts as a signaling hub sustaining epithelial progenitors and promoting tertiary lymphoid structure neogenesis, linking these hallmarks of thymic aging. Together, our findings reframe thymic involution as spatial stromal reorganization that links stromal remodeling to impaired thymopoiesis, central tolerance, and immune aging.

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Research summary

The study utilizes multi-omic spatial profiling to demonstrate that thymic aging involves a complex spatial reorganization of the stroma and the emergence of new microenvironments, rather than simple epithelial loss, thereby identifying specific stromal niches and signaling hubs (such as medullary fibroblasts) that drive impaired thymopoiesis and central tolerance. This work is relevant to longevity research because it elucidates the mechanistic root causes of immunosenescence—a fundamental hallmark of aging—by mapping the structural and functional decline of the thymus, which is critical for understanding how to maintain immune function and tolerance in aging organisms.

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