Dendritic cells control fibroblastic reticular network tension and lymph node expansion

Acton, Sophie E.; Farrugia, Aaron J.; Astarita, Jillian L.; Mourão-Sá, Diego; Jenkins, Robert P.; Nye, Emma; Hooper, Steven; Blijswijk, Janneke van; Rogers, Neil C.; Snelgrove, Kathryn J.; Rosewell, Ian; Moita, Luís F.; Stamp, Gordon; Turley, Shannon J.; Sahai, Erik; Sousa, Caetano Reis e

doi:10.1038/nature13814

Cited by 254 publications

(543 citation statements)

References 28 publications

(48 reference statements)

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“…43 More important, in the lymph node environment, Pdpn promotes actinomyosin contractility in fibroblastic reticular cells via the RhoA/C-ROCK signaling pathway. 13,77 Shifts in fibroblast contractility dependent on Pdpn binding status may be especially relevant in the fibrotic setting given the attention being given to the role of matrix stiffness and mechanotransduction in fibroblasts. 78 CD90 has been linked to efficient wound closure.…”

Section: Discussionmentioning

confidence: 99%

Altered Dermal Fibroblasts in Systemic Sclerosis Display Podoplanin and CD90

Nazari

Rice

Stifano

et al. 2016

The American Journal of Pathology

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Tissue injury triggers the activation and differentiation of multiple cell types to minimize damage and initiate repair processes. In systemic sclerosis, these repair processes appear to run unchecked, leading to aberrant remodeling and fibrosis of the skin and multiple internal organs, yet the fundamental pathological defect remains unknown. We describe herein a transition wherein the abundant CD34 þ dermal fibroblasts present in healthy human skin disappear in the skin of systemic sclerosis patients, and CD34 À , podoplanin þ , and CD90 þ fibroblasts appear. This transition is limited to the upper dermis in several inflammatory skin diseases, yet in systemic sclerosis, it can occur in all regions of the dermis. In vitro, primary dermal fibroblasts readily express podoplanin in response to the inflammatory stimuli tumor necrosis factor and IL-1b. Furthermore, we show that on acute skin injury in both human and murine settings, this transition occurs quickly, consistent with a response to inflammatory signaling. Transitioned fibroblasts partially resemble the cells that form the reticular networks in organized lymphoid tissues, potentially linking two areas of fibroblast research. These results allow for the visualization and quantification of a basic stage of fibroblast differentiation in inflammatory and fibrotic diseases in the skin. (Am J Pathol 2016, 186: 2650e2664; http://dx

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Section: Discussionmentioning

confidence: 99%

Altered Dermal Fibroblasts in Systemic Sclerosis Display Podoplanin and CD90

Nazari

Rice

Stifano

et al. 2016

The American Journal of Pathology

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“…How T cells use and modulate this pathway to achieve mechanosensing (76), as in the case of mesenchymal stem cells, remains to be understood. Interestingly, the lymph node itself is also mechanically active, because Rho inactivation in fibroblastic reticular cells enables lymph node expansion during inflammation (77). Understanding the mechanobiology of T-cell activation is important for immunotherapy design against cancer because the tumor microenvironment is known to undergo significant extracellular matrix remodeling and stiffness changes during disease progression (78).…”

Section: Discussionmentioning

confidence: 99%

Dynamic microtubules regulate cellular contractility during T-cell activation

Hui

Upadhyaya

2017

Proc. Natl. Acad. Sci. U.S.A.

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T-cell receptor (TCR) triggering and subsequent T-cell activation are essential for the adaptive immune response. Recently, multiple lines of evidence have shown that force transduction across the TCR complex is involved during TCR triggering, and that the T cell might use its force-generation machinery to probe the mechanical properties of the opposing antigen-presenting cell, giving rise to different signaling and physiological responses. Mechanistically, actin polymerization and turnover have been shown to be essential for force generation by T cells, but how these actin dynamics are regulated spatiotemporally remains poorly understood. Here, we report that traction forces generated by T cells are regulated by dynamic microtubules (MTs) at the interface. These MTs suppress Rho activation, nonmuscle myosin II bipolar filament assembly, and actin retrograde flow at the T-cell-substrate interface. Our results suggest a novel role of the MT cytoskeleton in regulating force generation during T-cell activation.T lymphocytes, central players in the adaptive immune response, are activated when T-cell receptors (TCRs) on their surface recognize cognate peptide-major histocompatibility complex (pMHC) expressed on the surface of antigen-presenting cells (APCs). A burst of actin polymerization is triggered upon TCR stimulation (1), leading to an enhancement of the cell/APC contact area as the T cell spreads over the surface of the APC (2) and the formation of a macromolecular protein assembly known as the immunological synapse (IS) (3, 4). Accompanying IS formation, T cells also undergo a rapid polarization of the microtubule (MT) cytoskeleton, within 1-2 min after initial contact, that facilitates directional secretion of cytokines and cytolytic factors toward the APC (5-7). Therefore, the contact zone between T cells and APCs is a site at which the MT and actin cytoskeletons could potentially interact to regulate signaling.Recent studies have established that T cells generate significant traction stresses at the cell-cell interface, albeit relatively weak compared with adherent cells (8-11). These forces, which peak 5-10 min after stimulation, facilitate T-cell activation, in part, by inducing conformational changes in the TCR-CD3 complex (12-15). Although actin polymerization/depolymerization dynamics are essential for T cells to maintain dynamic traction stresses and to drive calcium influx and integrin affinity maturation (9, 16, 17), the regulatory pathways that control these cytoskeletal forces are not completely understood. In particular, whether and how the polarized MT cytoskeleton interacts with the actin cytoskeleton and regulates force generation at the T-cell-APC contact remain open questions.MTs in the cell exist in two populations: dynamic/tyrosinated MTs and stable MTs that have undergone posttranslational modifications, including detyrosination and acetylation (18). Previous studies of T-cell activation have elucidated that microtubuleorganizing center (MTOC) translocation is associated with the formati...

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“…To more directly measure lymph flow in CLEC2-deficient mice, fluorescent beads were injected into the lymphatic circulation through a peripheral lymph node, and their passive flow through the efferent collecting lymphatic vessel was tracked ( Figure 1, O and P, and Supplemental Videos 1 and 2). For these studies, we used 4-week-old Clec2 fl/fl ; Pf4-Cre mice in which CLEC2 is deleted specifically from platelets because global CLEC2-deficient mice fail to develop normal lymph nodes (26,27), and Clec2 fl/fl ; Pf4-Cre mice exhibit delayed post-natal lethality, most likely due to incomplete deletion in the megakaryocyte (22). Real-time imaging of microparticles revealed lymphatic pulsation in both Clec2 fl/fl ; Pf4-Cre and control mice.…”

Section: Introductionmentioning

confidence: 99%