Immune cells adapt to distinct stem cell niches to govern tissue homeostasis

Parigi, S. M.; Sajjath, S. M.; Bell, C. J.; Yuan, S.; Olyntho, V. M.; Bonny, A. R.; Nakandakari-Higa, S.; Lira, S.; Mucida, D.; Victora, G. D.; Fuchs, E.

doi:10.64898/2026.01.28.701831

bioRxiv · 10.64898/2026.01.28.701831

Immune cells adapt to distinct stem cell niches to govern tissue homeostasis

Parigi, S. M.·Sajjath, S. M.·Bell, C. J.·Yuan, S.·Olyntho, V. M.·Bonny, A. R.·Nakandakari-Higa, S.·Lira, S.·Mucida, D.·Victora, G. D.·Fuchs, E.

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Abstract

Summary ParagraphIn adult tissues, epithelial stem cells exist within distinct residences, each endowing them with exclusive instructions for regenerative fitness under homeostasis and stress. Key components of these niches are immune cells, which classically protect the host against external and internal threats. Whether and how stem cell:immune cell crosstalk contributes to normal tissue biology remains less clear. Here, we discover functional adaptation of resident lymphocytes within two distinct skin stem cell niches and show that through this communication, each niche adjusts to meet diverse tissue demands. In the upper hair follicle, where microbial load is high, T cells express lymphotoxin-{beta} and stimulate adjacent receptor-positive epithelial stem cells to form an immune-competent niche that controls microbial expansion. By contrast, in the epidermis, these T cells produce amphiregulin to maintain continuous stem cell reconstitution of the skins barrier. Concomitantly, they express the immune checkpoint protein LAG-3, which autorestricts lymphocyte numbers, and hence amphiregulin levels, thereby preventing over-proliferative responses. Finally, when epidermal T cells are absent, dermal lymphocytes restore the imbalance by colonizing and adapting to their new niche. Our findings unveil functional specialization and homeostatic resilience of immune-stem cell niches, each tailored to suit the demands of distinct tissue microenvironments.

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Parigi, S. M., Sajjath, S. M., Bell, C. J., Yuan, S., Olyntho, V. M., Bonny, A. R., Nakandakari-Higa, S., Lira, S., Mucida, D., Victora, G. D., Fuchs, E.. 2026-01-31. Immune cells adapt to distinct stem cell niches to govern tissue homeostasis. https://doi.org/10.64898/2026.01.28.701831

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