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After immunogenic challenge, infiltrating and dividing lymphocytes markedly increase lymph node cellularity, leading to organ expansion (1,2). Here we report that the physical elasticity of lymph nodes is maintained in part by podoplanin (PDPN) signalling in stromal fibroblastic reticular cells (FRCs) and its modulation by CLEC-2 expressed on dendritic cells. We show in mouse cells that PDPN induces actomyosin contractility in FRCs via activation of RhoA/C and downstream Rho-associated protein kinase (ROCK). Engagement by CLEC-2 causes PDPN clustering and rapidly uncouples PDPN from RhoA/C activation, relaxing the actomyosin cytoskeleton and permitting FRC stretching. Notably, administration of CLEC-2 protein to immunized mice augments lymph node expansion. In contrast, lymph node expansion is significantly constrained in mice selectively lacking CLEC-2 expression in dendritic cells. Thus, the same dendritic cells that initiate immunity by presenting antigens to T lymphocytes (3) also initiate remodelling of lymph nodes by delivering CLEC-2 to FRCs. CLEC-2 modulation of PDPN signalling permits FRC network stretching and allows for the rapid lymph node expansion--driven by lymphocyte influx and proliferation--that is the critical hallmark of adaptive immunity., Lymph nodes are meeting places for T lymphocytes and antigen-presenting dendritic cells (1,2). T-cell-dendritic-cell interactions are supported by FRCs (4,5), a complex interconnected network that produces and ensheathes extracellular matrix [...]

Rho family GTPases such as Cdc42 are key regulators of essential cellular processes through their effects on cytoskeletal dynamics, signaling and gene expression. Rho GTPases modulate these functions by engaging a wide variety of downstream effectors. Among these effectors is the largely understudied Cdc42EP/BORG family of Cdc42 effectors. BORG proteins have been linked to actin and septin regulation, but their role in development and disease is only starting to emerge. Recently, Cdc42EP3/BORG2 was shown to coordinate actin and septin cytoskeleton rearrangements in cancer-associated fibroblasts (CAFs). Interestingly, Cdc42EP3 expression potentiated cellular responses to mechanical stimulation leading to signaling and transcriptional adaptations required for the emergence of a fully activated CAF phenotype. These findings uncover a novel role for the BORG/septin network in cancer. Here, we demonstrate that Cdc42EP3 function in CAFs relies on tight regulation by Cdc42. [ABSTRACT FROM AUTHOR]

Cell adhesion receptors are transmembrane proteins that bind cells to their environment. These proteins typically cluster into disk-shaped or linear structures. Here, we show that such clustering patterns spontaneously emerge when the receptor senses the membrane deformation gradient, for example, by reaching a lower-energy conformation when the membrane is tilted relative to the underlying binding substrate. Increasing the strength of the membrane gradient-sensing mechanism first yields isolated disk-shaped clusters and then long linear structures. Our theory is coherent with experimental estimates of the parameters, suggesting that a tilt-induced clustering mechanism is relevant in the context of cell adhesion.