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T lymphocytes must be produced throughout life, yet the thymus, where T lymphocytes are made, exhibits accelerated atrophy with age. Even in advanced atrophy, however, the thymus remains plastic, and can be regenerated by appropriate stimuli. Logically, thymic atrophy is thought to reflect senescent cell death, while regeneration requires proliferation of stem or progenitor cells, although evidence is scarce. Here we use conditional reporters to show that accelerated thymic atrophy reflects contraction of complex cell projections unique to cortical epithelial cells, while regeneration requires their regrowth.

Both atrophy and regeneration are independent of changes in epithelial cell number, suggesting that the size of the thymus is regulated primarily by rate-limiting morphological changes in cortical stroma, rather than by their cell death or proliferation.

Our data also suggest that cortical epithelial morphology is under the control of medullary stromal signals, revealing a previously unrecognized endocrine-paracrine signaling axis in the thymus. Like all blood cells, T lymphocytes are lost throughout life, and must be continuously replaced. The thymus is the primary site of post-natal T lymphopoiesis.