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

Abstract

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.

The influence of three-dimensional structure on naïve T cell homeostasis and aging

“…The requirement for an organoid (3D + stromal cells) for any longterm maintenance of the youthful phenotype has potential implications; 1) the maintenance of a youthful phenotype is an active process, 2) cellular crosstalk is essential but not sufficient for this maintenance and 3) structural integrity of LN is vital for T cell homeostasis. Although the organoid formation seeds T cell and FRCs into the environment at the same, which is somewhat distinct from true LN homeostasis where the FRC network is already in place (Kelch et al, 2019;Horsnell et al, 2022), our data imply that FRC may change their behavior in an environment with structural breakdown, providing different, less homeostatic signals.…”

Actin-driven protrusions generate rapid long-range membrane tension propagation in cells

“…Membrane tension is a central regulator of many fundamental biological processes (1–9). In the context of cell migration, membrane tension has been proposed to serve as a rapid long-range coordinator of information across the cell for a ‘winner-take-all’ in polarity establishment (10–12).…”

Lymph Node Fibroblast Phenotypes and Immune Crosstalk Regulated by Podoplanin Activity

“…S6a). We have shown previously that PDPN is a mechanical sensor in FRCs and is required to trigger FRC proliferation in response to increased mechanical strain as the lymph node begins to expand (38) which can explain the reduction in FRC numbers. The number of B and T lymphocytes was unchanged in PDGFR α mGFPΔPDPN mice in steady state, but all subsets were reduced in number post immunisation (Fig.…”