Lymph node homeostasis and adaptation to immune challenge resolved by fibroblast network mechanics

Harry L. Horsnell, Robert J. Tetley, Henry de Belly, Spyridon Makris, Lindsey J. Millward, Agnesska C. Benjamin, Lucas A. Heeringa, Charlotte M. de Winde, Ewa K. Paluch, Yanlan Mao, Sophie E. Acton

Research output: Contribution to journalArticleAcademicpeer-review

21 Citations (Scopus)


Emergent physical properties of tissues are not readily understood by reductionist studies of their constituent cells. Here, we show molecular signals controlling cellular, physical, and structural properties and collectively determine tissue mechanics of lymph nodes, an immunologically relevant adult tissue. Lymph nodes paradoxically maintain robust tissue architecture in homeostasis yet are continually poised for extensive expansion upon immune challenge. We find that in murine models of immune challenge, cytoskeletal mechanics of a cellular meshwork of fibroblasts determine tissue tension independently of extracellular matrix scaffolds. We determine that C-type lectin-like receptor 2 (CLEC-2)–podoplanin signaling regulates the cell surface mechanics of fibroblasts, providing a mechanically sensitive pathway to regulate lymph node remodeling. Perturbation of fibroblast mechanics through genetic deletion of podoplanin attenuates T cell activation. We find that increased tissue tension through the fibroblastic stromal meshwork is required to trigger the initiation of fibroblast proliferation and restore homeostatic cellular ratios and tissue structure through lymph node expansion.
Original languageEnglish
Pages (from-to)1169-1182
Number of pages14
JournalNature immunology
Issue number8
Early online date2022
Publication statusPublished - Aug 2022
Externally publishedYes

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