Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Mechanosensing in T lymphocyte activation.

ABSTRACT: Mechanical forces play an increasingly recognized role in modulating cell function. This report demonstrates mechanosensing by T cells, using polyacrylamide gels presenting ligands to CD3 and CD28. Naive CD4 T cells exhibited stronger activation, as measured by attachment and secretion of IL-2, with increasing substrate elastic modulus over the range of 10-200 kPa. By presenting these ligands on different surfaces, this report further demonstrates that mechanosensing is more strongly associated with CD3 rather than CD28 signaling. Finally, phospho-specific staining for Zap70 and Src family kinase proteins suggests that sensing of substrate rigidity occurs at least in part by processes downstream of T-cell receptor activation. The ability of T cells to quantitatively respond to substrate rigidly provides an intriguing new model for mechanobiology.

SUBMITTER: Judokusumo E

PROVIDER: S-EPMC3260692 | biostudies-literature | 2012 Jan

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

Mechanosensing in T lymphocyte activation.

Judokusumo Edward E Tabdanov Erdem E Kumari Sudha S Dustin Michael L ML Kam Lance C LC

Biophysical journal 20120101 2

Mechanical forces play an increasingly recognized role in modulating cell function. This report demonstrates mechanosensing by T cells, using polyacrylamide gels presenting ligands to CD3 and CD28. Naive CD4 T cells exhibited stronger activation, as measured by attachment and secretion of IL-2, with increasing substrate elastic modulus over the range of 10-200 kPa. By presenting these ligands on different surfaces, this report further demonstrates that mechanosensing is more strongly associated ...[more]

PMID: 22339876

Similar Datasets

Mechanosensing by Peyer's patch stroma regulates lymphocyte migration and mucosal antibody responses.

Project description:Fibroblastic reticular cells (FRCs) and their specialized collagen fibers termed 'conduits' form fundamental structural units supporting lymphoid tissues. In lymph nodes, conduits are known to transport interstitial fluid and small molecules from afferent lymphatics into the nodal parenchyma. However, the immunological contributions of conduit function have remained elusive. Here, we report that intestinal Peyer's patches (PPs) contain a specialized conduit system that directs the flow of water absorbed across the intestinal epithelium. Notably, PP FRCs responded to conduit fluid flow via the mechanosensitive ion channel Piezo1. Disruption of fluid flow or genetic deficiency of Piezo1 on CCL19-expressing stroma led to profound structural alterations in perivascular FRCs and associated high endothelial venules. This in turn impaired lymphocyte entry into PPs and initiation of mucosal antibody responses. These results identify a critical role for conduit-mediated fluid flow in the maintenance of PP homeostasis and mucosal immunity.

| S-EPMC7015178 | biostudies-literature

Mechanosensing through YAP controls T cell activation and metabolism.

Project description:Upon immunogenic challenge, lymph nodes become mechanically stiff as immune cells activate and proliferate within their encapsulated environments, and with resolution, they reestablish a soft baseline state. Here we show that sensing these mechanical changes in the microenvironment requires the mechanosensor YAP. YAP is induced upon activation and suppresses metabolic reprogramming of effector T cells. Unlike in other cell types in which YAP promotes proliferation, YAP in T cells suppresses proliferation in a stiffness-dependent manner by directly restricting the translocation of NFAT1 into the nucleus. YAP slows T cell responses in systemic viral infections and retards effector T cells in autoimmune diabetes. Our work reveals a paradigm whereby tissue mechanics fine-tune adaptive immune responses in health and disease.

| S-EPMC7398163 | biostudies-literature

Mechanosensing

Project description:On the significance of mechanosensing for seed development and maturation

| PRJEB44868 | ENA

Mechanosensing regulates plasmacytoid DCs activation in the skin through NRF2 activation

Project description:Plasmacytoid dendritic cells (pDCs) infiltrate the skin, chronically produce type I interferon (IFN-I) and promote skin lesions and fibrosis in autoimmune patients. However what controls their activation in the skin is unknown. Here, we report that increased stiffness, characteristic of the skin microenvironment, inhibits the production of IFN-I by TLR-activated pDCs. Mechanistically, mechanosensing activates stress pathways including the transcription factor NRF2, which, by triggering the pentose phosphate pathway, rewires glycolysis and reduces pyruvate levels, a product necessary for pDC responses. Modulating NRF2 expression in skin-infiltrating pDCs controlled the IFN-I response, leading to either resolution or the sustained activation of pathologic IFN-I pathway in the skin. Moreover, we observed that CXCL4, a pro-fibrotic chemokine that is elevated in fibrotic skin, was able to overcome stiffness-mediated IFN-I inhibition, allowing chronic IFN-I responses by pDCs in the skin. Furthermore, in the skin of patients with systemic sclerosis (SSc), although NRF2 was induced in skin-infiltrating pDCs as compared to blood pDCs, the IFN-response was maintained. Hence, these data identify a novel regulatory mechanism exerted by the skin microenvironment and identify points of dysregulation of this mechanism in patients with skin inflammation and fibrosis.

2024-12-02 | GSE282652 | GEO

Mechanosensing regulates plasmacytoid DCs activation in the skin through NRF2 activation

Project description:Plasmacytoid dendritic cells (pDCs) infiltrate the skin, chronically produce type I interferon (IFN-I) and promote skin lesions and fibrosis in autoimmune patients. However, what controls their activation in the skin is unknown. Here, we report that increased stiffness, characteristic of the skin microenvironment, inhibits the production of IFN-I by TLR-activated pDCs. Mechanistically, mechanosensing activates stress pathways including the transcription factor NRF2, which, by triggering the pentose phosphate pathway, rewires glycolysis and reduces pyruvate levels, a product necessary for pDC responses. Modulating NRF2 expression in skin-infiltrating pDCs controlled the IFN-I response, leading to either resolution or the sustained activation of pathologic IFN-I pathway in the skin. Moreover, we observed that CXCL4, a pro-fibrotic chemokine that is elevated in fibrotic skin, was able to overcome stiffness-mediated IFN-I inhibition, allowing chronic IFN-I responses by pDCs in the skin. Furthermore, in the skin of patients with systemic sclerosis (SSc), although NRF2 was induced in skin-infiltrating pDCs as compared to blood pDCs, the IFN-response was maintained. Hence, these data identify a novel regulatory mechanism exerted by the skin microenvironment and identify points of dysregulation of this mechanism in patients with skin inflammation and fibrosis.

2024-11-28 | GSE282697 | GEO

Stress-dependent activation of myosin in the heart requires thin filament activation and thick filament mechanosensing.

Project description:Myosin-based regulation in the heart muscle modulates the number of myosin motors available for interaction with calcium-regulated thin filaments, but the signaling pathways mediating the stronger contraction triggered by stretch between heartbeats or by phosphorylation of the myosin regulatory light chain (RLC) remain unclear. Here, we used RLC probes in demembranated cardiac trabeculae to investigate the molecular structural basis of these regulatory pathways. We show that in relaxed trabeculae at near-physiological temperature and filament lattice spacing, the RLC-lobe orientations are consistent with a subset of myosin motors being folded onto the filament surface in the interacting-heads motif seen in isolated filaments. The folded conformation of myosin is disrupted by cooling relaxed trabeculae, similar to the effect induced by maximal calcium activation. Stretch or increased RLC phosphorylation in the physiological range have almost no effect on RLC conformation at a calcium concentration corresponding to that between beats. These results indicate that in near-physiological conditions, the folded myosin motors are not directly switched on by RLC phosphorylation or by the titin-based passive tension at longer sarcomere lengths in the absence of thin filament activation. However, at the higher calcium concentrations that activate the thin filaments, stretch produces a delayed activation of folded myosin motors and force increase that is potentiated by RLC phosphorylation. We conclude that the increased contractility of the heart induced by RLC phosphorylation and stretch can be explained by a calcium-dependent interfilament signaling pathway involving both thin filament sensitization and thick filament mechanosensing.

| S-EPMC8072254 | biostudies-literature

Platelet mechanosensing of substrate stiffness during clot formation mediates adhesion, spreading, and activation.

Project description:As platelets aggregate and activate at the site of vascular injury to stem bleeding, they are subjected to a myriad of biochemical and biophysical signals and cues. As clot formation ensues, platelets interact with polymerizing fibrin scaffolds, exposing platelets to a large range of mechanical microenvironments. Here, we show for the first time (to our knowledge) that platelets, which are anucleate cellular fragments, sense microenvironmental mechanical properties, such as substrate stiffness, and transduce those cues into differential biological signals. Specifically, as platelets mechanosense the stiffness of the underlying fibrin/fibrinogen substrate, increasing substrate stiffness leads to increased platelet adhesion and spreading. Importantly, adhesion on stiffer substrates also leads to higher levels of platelet activation, as measured by integrin ?IIb?3 activation, ?-granule secretion, and procoagulant activity. Mechanistically, we determined that Rac1 and actomyosin activity mediate substrate stiffness-dependent platelet adhesion, spreading, and activation to different degrees. This capability of platelets to mechanosense microenvironmental cues in a growing thrombus or hemostatic plug and then mechanotransduce those cues into differential levels of platelet adhesion, spreading, and activation provides biophysical insight into the underlying mechanisms of platelet aggregation and platelet activation heterogeneity during thrombus formation.

| S-EPMC4210024 | biostudies-literature

Abnormal mechanosensing and cofilin activation promote the progression of ascending aortic aneurysms in mice.

Project description:Smooth muscle cells (SMCs) and the extracellular matrix (ECM) are intimately associated in the aortic wall. Fbln4(SMKO) mice with an SMC-specific deletion of the Fbln4 gene, which encodes the vascular ECM component fibulin-4, develop ascending aortic aneurysms that have increased abundance of angiotensin-converting enzyme (ACE); inhibiting angiotensin II signaling within the first month of life prevents aneurysm development. We used comparative proteomics analysis of Fbln4(SMKO) aortas from postnatal day (P) 1 to P30 mice to identify key molecules involved in aneurysm initiation and expansion. At P14, the actin depolymerizing factor cofilin was dephosphorylated and thus activated, and at P7, the abundance of slingshot-1 (SSH1) phosphatase, an activator of cofilin, was increased, leading to actin cytoskeletal remodeling. Also, by P7, biomechanical changes and underdeveloped elastic lamina-SMC connections were evident, and the abundance of early growth response 1 (Egr1), a mechanosensitive transcription factor that stimulates ACE expression, was increased, which was before the increases in ACE abundance and cofilin activation. Postnatal deletion of Fbln4 in SMCs at P7 prevented cofilin activation and aneurysm formation, suggesting that these processes required disruption of elastic lamina-SMC connections. Phosphoinositide 3-kinase (PI3K) is involved in the angiotensin II-mediated activation of SSH1, and administration of PI3K inhibitors from P7 to P30 decreased SSH1 abundance and prevented aneurysms. These results suggest that aneurysm formation arises from abnormal mechanosensing of SMCs resulting from the loss of elastic lamina-SMC connections and from increased SSH1 and cofilin activity, which may be potential therapeutic targets for treating ascending aortic aneurysms.

| S-EPMC5572214 | biostudies-literature

Mechanosensing regulates plasmacytoid DCs activation in the skin through NRF2 activation

Project description:Mechanosensing regulates plasmacytoid DCs activation in the skin through NRF2 activation

| PRJNA1189818 | ENA

Mechanosensing regulates plasmacytoid DCs activation in the skin through NRF2 activation

Project description:Mechanosensing regulates plasmacytoid DCs activation in the skin through NRF2 activation

| PRJNA1189544 | ENA