scholarly journals cAMP Bursts Control T Cell Directionality by Actomyosin Cytoskeleton Remodeling

2021 ◽  
Vol 9 ◽  
Author(s):  
Morgane Simao ◽  
Fabienne Régnier ◽  
Sarah Taheraly ◽  
Achille Fraisse ◽  
Rachida Tacine ◽  
...  
Keyword(s):  
T Cell ◽  
T Lymphocyte ◽  
Physical Environment ◽  
Cell Imaging ◽  
Morphological Changes ◽  
Leading Edge ◽  
Lymphocyte Migration ◽  
Dynamic Cell ◽  
Cytoskeleton Remodeling ◽  
Actomyosin Cytoskeleton

T lymphocyte migration is an essential step to mounting an efficient immune response. The rapid and random motility of these cells which favors their sentinel role is conditioned by chemokines as well as by the physical environment. Morphological changes, underlaid by dynamic actin cytoskeleton remodeling, are observed throughout migration but especially when the cell modifies its trajectory. However, the signaling cascade regulating the directional changes remains largely unknown. Using dynamic cell imaging, we investigated in this paper the signaling pathways involved in T cell directionality. We monitored cyclic adenosine 3′-5′ monosphosphate (cAMP) variation concomitantly with actomyosin distribution upon T lymphocyte migration and highlighted the fact that spontaneous bursts in cAMP starting from the leading edge, are sufficient to promote actomyosin redistribution triggering trajectory modification. Although cAMP is commonly considered as an immunosuppressive factor, our results suggest that, when transient, it rather favors the exploratory behavior of T cells.

scholarly journals cAMP bursts control T cell directionality by actin cytoskeleton remodeling

2020 ◽  
Author(s):  
Morgane Simao ◽  
Fabienne Régnier ◽  
Sarah Taheraly ◽  
Achille Fraisse ◽  
Rachida Tacine ◽  
...  
Keyword(s):  
T Cell ◽  
Actin Cytoskeleton ◽  
T Lymphocyte ◽  
Physical Environment ◽  
Cell Imaging ◽  
Morphological Changes ◽  
Leading Edge ◽  
Lymphocyte Migration ◽  
Dynamic Cell ◽  
Cytoskeleton Remodeling

AbstractT lymphocyte migration is an essential step to mounting an efficient immune response. The rapid and random motility of these cells which favors their sentinel role is conditioned by chemokines as well as by the physical environment. Morphological changes, underlaid by dynamic actin cytoskeleton remodeling, are observed throughout migration but especially when the cell modifies its trajectory. Using dynamic cell imaging, we investigated the signaling pathways involved in T cell directionality control. We monitored cAMP variation concomitantly with actin distribution upon T lymphocyte migration and highlighted the fact that spontaneous bursts in cAMP starting from the leading edge, are sufficient to promote stable actin redistribution triggering trajectory modification.

scholarly journals Different TCR-induced T lymphocyte responses are potentiated by stiffness with variable sensitivity

eLife ◽  
2017 ◽  
Vol 6 ◽  
Author(s):  
Michael Saitakis ◽  
Stéphanie Dogniaux ◽  
Christel Goudot ◽  
Nathalie Bufi ◽  
Sophie Asnacios ◽  
...  
Keyword(s):  
Cell Cycle ◽  
T Cells ◽  
T Cell ◽  
T Lymphocyte ◽  
Cytokine Production ◽  
Morphological Changes ◽  
The Body ◽  
Lymphocyte Migration ◽  
Cell Functions ◽  
Wide Range

T cells are mechanosensitive but the effect of stiffness on their functions is still debated. We characterize herein how human primary CD4+ T cell functions are affected by stiffness within the physiological Young’s modulus range of 0.5 kPa to 100 kPa. Stiffness modulates T lymphocyte migration and morphological changes induced by TCR/CD3 triggering. Stiffness also increases TCR-induced immune system, metabolism and cell-cycle-related genes. Yet, upon TCR/CD3 stimulation, while cytokine production increases within a wide range of stiffness, from hundreds of Pa to hundreds of kPa, T cell metabolic properties and cell cycle progression are only increased by the highest stiffness tested (100 kPa). Finally, mechanical properties of adherent antigen-presenting cells modulate cytokine production by T cells. Together, these results reveal that T cells discriminate between the wide range of stiffness values found in the body and adapt their responses accordingly.

scholarly journals Formin-like 1 mediates effector T cell trafficking to inflammatory sites to enable T cell-mediated autoimmunity

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Scott B Thompson ◽  
Adam M Sandor ◽  
Victor Lui ◽  
Jeffrey W Chung ◽  
Monique M Waldman ◽  
...  
Keyword(s):  
T Cell ◽  
Actin Polymerization ◽  
Morphological Changes ◽  
Adaptive Immune System ◽  
Cell Entry ◽  
Cell Trafficking ◽  
Lymphocyte Migration ◽  
Knock Out ◽  
T Cell Trafficking ◽  
Effector T Cell

Lymphocyte migration is essential for the function of the adaptive immune system, and regulation of T cell entry into tissues is an effective therapy in autoimmune diseases. Little is known about the specific role of cytoskeletal effectors that mediate mechanical forces and morphological changes essential for migration in complex environments. We developed a new Formin-like-1 (FMNL1) knock-out mouse model and determined that the cytoskeletal effector FMNL1 is selectively required for effector T cell trafficking to inflamed tissues, without affecting naïve T cell entry into secondary lymphoid organs. Here, we identify a FMNL1-dependent mechanism of actin polymerization at the back of the cell that enables migration of the rigid lymphocyte nucleus through restrictive barriers. Furthermore, FMNL1-deficiency impairs the ability of self-reactive effector T cells to induce autoimmune disease. Overall, our data suggest that FMNL1 may be a potential therapeutic target to specifically modulate T cell trafficking to inflammatory sites.

Mechanisms of chemokine and antigen-dependent T-lymphocyte navigation

2009 ◽  
Vol 418 (1) ◽  
pp. 13-27 ◽  
Author(s):  
Stephen G. Ward ◽  
Federica M. Marelli-Berg
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Lymphocyte ◽  
Chemokine Receptors ◽  
Inflammatory Diseases ◽  
Transplant Rejection ◽  
Small Gtpases ◽  
Cell Trafficking ◽  
Lymphocyte Migration ◽  
T Cell Trafficking

T-lymphocyte trafficking is targeted to specific organs by selective molecular interactions depending on their differentiation and functional properties. Specific chemokine receptors have been associated with organ-specific trafficking of memory and effector T-cells, as well as the recirculation of naïve T-cells to secondary lymphoid organs. In addition to the acquisition of tissue-selective integrins and chemokine receptors, an additional level of specificity for T-cell trafficking into the tissue is provided by specific recognition of antigen displayed by the endothelium involving the TCRs (T-cell antigen receptors) and co-stimulatory receptors. Activation of PI3K (phosphoinositide 3-kinase) is a robust signalling event shared by most chemokine receptors as well as the TCR and co-stimulatory receptors, contributing to several aspects of T-lymphocyte homing as well as actin reorganization and other components of the general migratory machinery. Accordingly, inhibition of PI3K has been considered seriously as a potential therapeutic strategy by which to combat various T-lymphocyte-dependent pathologies, including autoimmune and inflammatory diseases, as well as to prevent transplant rejection. However, there is substantial evidence for PI3K-independent mechanisms that facilitate T-lymphocyte migration. In this regard, several other signalling-pathway components, including small GTPases, PLC (phospholipase C) and PKC (protein kinase C) isoforms, have also been implicated in T-lymphocyte migration in response to chemokine stimulation. The present review will therefore examine the PI3K-dependent and -independent signal-transduction pathways involved in T-cell migration during distinct modes of T-cell trafficking in response to either chemokines or the TCR and co-stimulatory molecules.

T Lymphocyte Migration: The Influence of Interactions via Adhesion Molecules, the T Cell Receptor, and Cytokines

1995 ◽  
Vol 15 (3-4) ◽  
pp. 285-316 ◽  
Author(s):  
Dan Hauzenberger ◽  
Julius Klominek ◽  
Sten-Erik Bergstrom ◽  
Karl-Gosta Sundqvist
Keyword(s):  
T Cell ◽  
Adhesion Molecules ◽  
T Cell Receptor ◽  
T Lymphocyte ◽  
Cell Receptor ◽  
Lymphocyte Migration

scholarly journals BRG1 Mediates Nephronectin Activation in Hepatocytes to Promote T Lymphocyte Infiltration in ConA-Induced Hepatitis

2021 ◽  
Vol 8 ◽  
Author(s):  
Wenxuan Hong ◽  
Ming Kong ◽  
Mengwen Qi ◽  
Hui Bai ◽  
Zhiwen Fan ◽  
...  
Keyword(s):  
T Cell ◽  
Acute Hepatitis ◽  
T Lymphocyte ◽  
Lymphocyte Migration ◽  
Cell Homing ◽  
Biopsy Specimens ◽  
T Cell Homing ◽  
Lectin Family ◽  
Massive Accumulation

Fulminant hepatitis (FH) is a major cause of acute liver failure. Concanavalin A (ConA) belongs to the lectin family and is frequently used as an inducer of FH in animal models. ConA induced FH is characterized by massive accumulation of T lymphocytes in the liver. A host of chemoattractive substances are known to promote T cell homing to the liver during acute hepatitis. Here we investigated the involvement of Brahma-related gene 1 (BRG1), a chromatin remodeling protein, in FH. BRG1-flox mice were crossed to Alb-Cre mice to generate hepatocyte conditional BRG1 knockout (LKO) mice. The mice were peritoneally injected with a single dose of ConA to induce FH. BRG1 deficiency mitigated ConA-induced FH in mice. Consistently, there were fewer T lymphocyte infiltrates in the LKO livers compared to the wild type (WT) livers paralleling downregulation of T cell specific cytokines. Further analysis revealed that BRG1 deficiency repressed the expression of several chemokines critical for T cell homing including nephronectin (Npnt). BRG1 knockdown blocked the induction of Npnt in hepatocytes and attenuated T lymphocyte migration in vitro, which was reversed by the addition of recombinant nephronectin. Mechanistically, BRG1 interacted with β-catenin to directly bind to the Npnt promoter and activate Npnt transcription. Importantly, a positive correlation between infiltration of CD3+ T lymphocyes and nephronectin expression was detected in human acute hepatitis biopsy specimens. In conclusion, our data identify a novel role for BRG1 as a promoter of T lymphocyte trafficking by activating Npnt transcription in hepatocytes. Targeting the BRG1-Npnt axis may yield novel therapeutic solutions for FH.

scholarly journals The tumor suppressor Adenomatous polyposis coli modulates T lymphocyte migration

2021 ◽  
Author(s):  
Marta Mastrogiovanni ◽  
Pablo Vargas ◽  
Thierry Rose ◽  
Céline Cuche ◽  
Marie Juzans ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Migration ◽  
T Cell ◽  
Tumor Immunity ◽  
T Lymphocyte ◽  
Adenomatous Polyposis ◽  
Polyposis Coli ◽  
Lymphocyte Migration ◽  
T Cell Migration ◽  
And Migration

Adenomatous polyposis coli (APC) is a tumor suppressor whose mutations underlie familial adenomatous polyposis (FAP) and colorectal cancer. Although its role in intestinal epithelial cells is well characterized, APC importance for anti-tumor immunity is ill defined. Besides its role in Wnt/β-catenin signaling, APC regulates cytoskeleton organization, cell polarity and migration in various cells types. Here we address whether APC plays a role in T lymphocyte migration, a key step of anti-tumor immune responses. Using a series of cell biology tools, we measured migration of primary T cells obtained from FAP patients carrying APC mutations. FAP T cells showed decreased chemotaxis through micropores or endothelial cell monolayers. Concomitantly, they presented lower expression of the VLA-4 (α4β1) integrin at the cell surface. Notably, adhesion and migration in micro- fabricated channels were specifically reduced when surfaces were coated with VLA-4 ligands, indicating that defective adhesion could lead to decreased T cell migration. To further dissect the cellular mechanisms underpinning APC-mediated defects, we depleted APC in the CEM T cell line. We found that APC is critical for VLA-4-dependent adhesion, and acto-myosin and microtubule organization in migrating cells. APC-silenced CEM cells preferentially adopt an ameboid-like migration, lacking adhesive filopodia and continuously extending and retracting unstructured membrane protrusions. These findings underscore a role of APC in T cell migration via modulation of integrin- dependent adhesion and cytoskeleton reorganization. Hence, APC mutations in FAP patients not only unbalance epithelial homeostasis, driving intestinal neoplasms, but also impair T cell migration, potentially leading to inefficient T cell-mediated anti-tumor immunity.

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