scholarly journals GSK3β Interacts With CRMP2 and Notch1 and Controls T-Cell Motility

2021 ◽  
Vol 12 ◽  
Author(s):  
Mobashar Hussain Urf Turabe Fazil ◽  
Praseetha Prasannan ◽  
Brandon Han Siang Wong ◽  
Amuthavalli Kottaiswamy ◽  
Nur Syazwani Binte Mohamed Salim ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Motility ◽  
Nuclear Translocation ◽  
Glycogen Synthase ◽  
Immune Surveillance ◽  
Lymphatic Vessels ◽  
Adaptive Immune Response ◽  
Microtubule Organizing Center ◽  
Peripheral Tissues

The trafficking of T-cells through peripheral tissues and into afferent lymphatic vessels is essential for immune surveillance and an adaptive immune response. Glycogen synthase kinase 3β (GSK3β) is a serine/threonine kinase and regulates numerous cell/tissue-specific functions, including cell survival, metabolism, and differentiation. Here, we report a crucial involvement of GSK3β in T-cell motility. Inhibition of GSK3β by CHIR-99021 or siRNA-mediated knockdown augmented the migratory behavior of human T-lymphocytes stimulated via an engagement of the T-cell integrin LFA-1 with its ligand ICAM-1. Proteomics and protein network analysis revealed ongoing interactions among GSK3β, the surface receptor Notch1 and the cytoskeletal regulator CRMP2. LFA-1 stimulation in T-cells reduced Notch1-dependent GSK3β activity by inducing phosphorylation at Ser9 and its nuclear translocation accompanied by the cleaved Notch1 intracellular domain and decreased GSK3β-CRMP2 association. LFA-1-induced or pharmacologic inhibition of GSK3β in T-cells diminished CRMP2 phosphorylation at Thr514. Although substantial amounts of CRMP2 were localized to the microtubule-organizing center in resting T-cells, this colocalization of CRMP2 was lost following LFA-1 stimulation. Moreover, the migratory advantage conferred by GSK3β inhibition in T-cells by CHIR-99021 was lost when CRMP2 expression was knocked-down by siRNA-induced gene silencing. We therefore conclude that GSK3β controls T-cell motility through interactions with CRMP2 and Notch1, which has important implications in adaptive immunity, T-cell mediated diseases and LFA-1-targeted therapies.

scholarly journals Structure and Immune Function of Afferent Lymphatics and Their Mechanistic Contribution to Dendritic Cell and T Cell Trafficking

Cells ◽  
2021 ◽  
Vol 10 (5) ◽  
pp. 1269
Author(s):  
Jorge Arasa ◽  
Victor Collado-Diaz ◽  
Cornelia Halin
Keyword(s):  
T Cells ◽  
Cell Migration ◽  
T Cell ◽  
Molecular Mechanisms ◽  
Immune Surveillance ◽  
Lymphatic Vessels ◽  
Time Lapse ◽  
Cell Trafficking ◽  
Peripheral Tissues ◽  
T Cell Migration

Afferent lymphatic vessels (LVs) mediate the transport of antigen and leukocytes to draining lymph nodes (dLNs), thereby serving as immunologic communication highways between peripheral tissues and LNs. The main cell types migrating via this route are antigen-presenting dendritic cells (DCs) and antigen-experienced T cells. While DC migration is important for maintenance of tolerance and for induction of protective immunity, T cell migration through afferent LVs contributes to immune surveillance. In recent years, great progress has been made in elucidating the mechanisms of lymphatic migration. Specifically, time-lapse imaging has revealed that, upon entry into capillaries, both DCs and T cells are not simply flushed away with the lymph flow, but actively crawl and patrol and even interact with each other in this compartment. Detachment and passive transport to the dLN only takes place once the cells have reached the downstream, contracting collecting vessel segments. In this review, we describe how the anatomy of the lymphatic network supports leukocyte trafficking and provide updated knowledge regarding the cellular and molecular mechanisms responsible for lymphatic migration of DCs and T cells. In addition, we discuss the relevance of DC and T cell migration through afferent LVs and its presumed implications on immunity.

scholarly journals Intermittent Ca2+ signals mediated by Orai1 regulate basal T cell motility

2017 ◽  
Author(s):  
Tobias X. Dong ◽  
Shivashankar Othy ◽  
Milton L. Greenberg ◽  
Amit Jairaman ◽  
Chijioke Akunwafo ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Motility ◽  
Immune Surveillance ◽  
Cellular Motility ◽  
Average Cell ◽  
Cell Functions ◽  
Human T Cells

AbstractCa2+ influx through Orai1 channels is crucial for several T cell functions, but a role in regulating basal cellular motility has not been described. Here we show that inhibition of Orai1 channel activity increases average cell velocities by reducing the frequency of pauses in human T cells migrating through confined spaces, even in the absence of extrinsic cell contacts or antigen recognition. Utilizing a novel ratiometric genetically encoded cytosolic Ca2+ indicator, Salsa6f, which permits real-time monitoring of cytosolic Ca2+ along with cell motility, we show that spontaneous pauses during T cell motility in vitro and in vivo coincide with episodes of cytosolic Ca2+ signaling. Furthermore, lymph node T cells exhibited two types of spontaneous Ca2+ transients: short-duration “sparkles” and longer duration global signals. Our results demonstrate that spontaneous and self-peptide MHC-dependent activation of Orai1 ensures random walk behavior in T cells to optimize immune surveillance.

scholarly journals Intermittent Ca2+ signals mediated by Orai1 regulate basal T cell motility

eLife ◽  
2017 ◽  
Vol 6 ◽  
Author(s):  
Tobias X Dong ◽  
Shivashankar Othy ◽  
Milton L Greenberg ◽  
Amit Jairaman ◽  
Chijioke Akunwafo ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Motility ◽  
Immune Surveillance ◽  
Cellular Motility ◽  
Average Cell ◽  
Cell Functions ◽  
Human T Cells

Ca2+ influx through Orai1 channels is crucial for several T cell functions, but a role in regulating basal cellular motility has not been described. Here, we show that inhibition of Orai1 channel activity increases average cell velocities by reducing the frequency of pauses in human T cells migrating through confined spaces, even in the absence of extrinsic cell contacts or antigen recognition. Utilizing a novel ratiometric genetically encoded cytosolic Ca2+ indicator, Salsa6f, which permits real-time monitoring of cytosolic Ca2+ along with cell motility, we show that spontaneous pauses during T cell motility in vitro and in vivo coincide with episodes of cytosolic Ca2+ signaling. Furthermore, lymph node T cells exhibited two types of spontaneous Ca2+ transients: short-duration ‘sparkles’ and longer duration global signals. Our results demonstrate that spontaneous and self-peptide MHC-dependent activation of Orai1 ensures random walk behavior in T cells to optimize immune surveillance.

scholarly journals TRM Integrins CD103 and CD49a Differentially Support Adherence and Motility After Resolution of Influenza Virus Infection

2020 ◽  
Author(s):  
Emma C Reilly ◽  
Kris Lambert Emo ◽  
Patrick M Buckley ◽  
Nicholas S Reilly ◽  
Francisco A Chaves ◽  
...  
Keyword(s):  
T Cells ◽  
Influenza Virus ◽  
T Cell ◽  
Virus Infection ◽  
Cell Surface ◽  
Cell Motility ◽  
Influenza Virus Infection ◽  
Influenza Viruses ◽  
Peripheral Tissues

AbstractTissue resident memory CD8 T (TRM) cells are a unique immune memory subset that develops and remains in peripheral tissues at the site of infection, providing future host resistance upon re-exposure to that pathogen. In the pulmonary system, TRM are identified through S1P antagonist CD69 and expression of integrins CD103/β7 and CD49a/CD29(β1). Contrary to the established role of CD69 on CD8 T cells, the functions of CD103 and CD49a on this population are not well defined. This study examines the expression patterns and functions of CD103 and CD49a with a specific focus on their impact on T cell motility during influenza virus infection. We show that the TRM cell surface phenotype develops by two-weeks post-infection and that each integrin contributes a distinct function regulating CD8 T cell motility both in vitro and in vivo, with CD49a facilitating migration and CD103 limiting motility through tethering. These results demonstrate for the first time how CD103 and CD49a differentially impact adherence and migration in the tissue, likely affecting overall retention, maintenance of TRM, and host protection.Significance StatementCurrent influenza vaccination strategies require annual immunizations, with fairly low efficacy rates. One technique to improve protection against a greater breadth of influenza viruses is to elicit broadly cross-reactive cell-mediated immunity and generate a local population of cytotoxic T cells to respond to conserved regions of circulating viruses. However, this approach requires improved understanding of how these cells migrate within and attach to the tissue, in order to persist and offer long-term immunity. This study investigates how receptors on the T cell surface impact the cell’s ability to interact with the tissue and provide evidence for which of these receptors are essential for protection. Furthermore, these studies reveal functional in vivo mechanisms of cellular markers used to characterize TRM.

scholarly journals Cell-intrinsic activation of Orai1 regulates human T cell motility

2017 ◽  
Author(s):  
Tobias X. Dong ◽  
Milton L. Greenberg ◽  
Sabrina Leverrier ◽  
Ying Yu ◽  
Ian Parker ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Lymph Nodes ◽  
Cell Motility ◽  
Cell Function ◽  
Immune Surveillance ◽  
Dominant Negative ◽  
Human T Cell ◽  
A Cell

AbstractCa2+ signaling through the store-operated Ca2+ channel, Orai1, is crucial for T cell function, but a role in regulating T cell motility in lymph nodes has not been previously reported. Tracking human T cells in immunodeficient mouse lymph nodes and in microfabricated PDMS channels, we show that inhibition of Orai1 channel activity with a dominant-negative Orai1-E106A construct increases average T cell velocities by reducing the frequency of pauses in motile T cells. Orai1-dependent motility arrest occurs spontaneously during confined motility in vitro, even in the absence of extrinsic cell contacts or antigen recognition. Utilizing a novel ratiometric genetically encoded cytosolic Ca2+ indicator, Salsa6f, we show these spontaneous pauses during T cell motility in vitro coincide with episodes of spontaneous cytosolic Ca2+ signaling. Our results demonstrate that Orai1, activated in a cell-intrinsic manner, regulates T cell motility patterns that accompany immune surveillance.

scholarly journals The Diverse Roles of γδ T Cells in Cancer: From Rapid Immunity to Aggressive Lymphoma

Cancers ◽  
2021 ◽  
Vol 13 (24) ◽  
pp. 6212
Author(s):  
Susann Schönefeldt ◽  
Tamara Wais ◽  
Marco Herling ◽  
Satu Mustjoki ◽  
Vasileios Bekiaris ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Transformation ◽  
Immune Surveillance ◽  
Treatment Strategies ◽  
Γδ T Cells ◽  
Aggressive Lymphoma ◽  
Γδ T Cell ◽  
Independent Manner ◽  
Peripheral Tissues

γδ T cells are unique players in shaping immune responses, lying at the intersection between innate and adaptive immunity. Unlike conventional αβ T cells, γδ T cells largely populate non-lymphoid peripheral tissues, demonstrating tissue specificity, and they respond to ligands in an MHC-independent manner. γδ T cells display rapid activation and effector functions, with a capacity for cytotoxic anti-tumour responses and production of inflammatory cytokines such as IFN-γ or IL-17. Their rapid cytotoxic nature makes them attractive cells for use in anti-cancer immunotherapies. However, upon transformation, γδ T cells can give rise to highly aggressive lymphomas. These rare malignancies often display poor patient survival, and no curative therapies exist. In this review, we discuss the diverse roles of γδ T cells in immune surveillance and response, with a particular focus on cancer immunity. We summarise the intriguing dichotomy between pro- and anti-tumour functions of γδ T cells in solid and haematological cancers, highlighting the key subsets involved. Finally, we discuss potential drivers of γδ T-cell transformation, summarising the main γδ T-cell lymphoma/leukaemia entities, their clinical features, recent advances in mapping their molecular and genomic landscapes, current treatment strategies and potential future targeting options.

scholarly journals A Skin-selective Homing Mechanism for Human Immune Surveillance T Cells

2004 ◽  
Vol 199 (9) ◽  
pp. 1265-1275 ◽  
Author(s):  
Patrick Schaerli ◽  
Lisa Ebert ◽  
Katharina Willimann ◽  
Andrea Blaser ◽  
Regula Stuber Roos ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Peripheral Blood ◽  
Transforming Growth Factor ◽  
Immune Surveillance ◽  
T Cell Subsets ◽  
Healthy Skin ◽  
Colon Tissue ◽  
Peripheral Tissues ◽  
Selective Ligand

Effective immune surveillance is essential for maintaining protection and homeostasis of peripheral tissues. However, mechanisms controlling memory T cell migration to peripheral tissues such as the skin are poorly understood. Here, we show that the majority of human T cells in healthy skin express the chemokine receptor CCR8 and respond to its selective ligand I-309/CCL1. These CCR8+ T cells are absent in small intestine and colon tissue, and are extremely rare in peripheral blood, suggesting healthy skin as their physiological target site. Cutaneous CCR8+ T cells are preactivated and secrete proinflammatory cytokines such as tumor necrosis factor–α and interferon-γ, but lack markers of cytolytic T cells. Secretion of interleukin (IL)-4, IL-10, and transforming growth factor–β was low to undetectable, arguing against a strict association of CCR8 expression with either T helper cell 2 or regulatory T cell subsets. Potential precursors of skin surveillance T cells in peripheral blood may correspond to the minor subset of CCR8+CD25− T cells. Importantly, CCL1 is constitutively expressed at strategic cutaneous locations, including dermal microvessels and epidermal antigen-presenting cells. For the first time, these findings define a chemokine system for homeostatic T cell traffic in normal human skin.

scholarly journals IFNγ-activated dermal lymphatic vessels inhibit cytotoxic T cells in melanoma and inflamed skin

2018 ◽  
Vol 215 (12) ◽  
pp. 3057-3074 ◽  
Author(s):  
Ryan S. Lane ◽  
Julia Femel ◽  
Alec P. Breazeale ◽  
Christopher P. Loo ◽  
Guillaume Thibault ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Protective Immunity ◽  
Cytotoxic T Cells ◽  
Lymphatic Vessels ◽  
Cd8 T Cell ◽  
Tumor Control ◽  
Peripheral Tissues ◽  
Tumor Microenvironments ◽  
Cell Accumulation

Mechanisms of immune suppression in peripheral tissues counteract protective immunity to prevent immunopathology and are coopted by tumors for immune evasion. While lymphatic vessels facilitate T cell priming, they also exert immune suppressive effects in lymph nodes at steady-state. Therefore, we hypothesized that peripheral lymphatic vessels acquire suppressive mechanisms to limit local effector CD8+ T cell accumulation in murine skin. We demonstrate that nonhematopoietic PD-L1 is largely expressed by lymphatic and blood endothelial cells and limits CD8+ T cell accumulation in tumor microenvironments. IFNγ produced by tissue-infiltrating, antigen-specific CD8+ T cells, which are in close proximity to tumor-associated lymphatic vessels, is sufficient to induce lymphatic vessel PD-L1 expression. Disruption of IFNγ-dependent crosstalk through lymphatic-specific loss of IFNγR boosts T cell accumulation in infected and malignant skin leading to increased viral pathology and tumor control, respectively. Consequently, we identify IFNγR as an immunological switch in lymphatic vessels that balances protective immunity and immunopathology leading to adaptive immune resistance in melanoma.

scholarly journals Glycogen synthase kinase 3 (GSK-3) controls T-cell motility and interactions with antigen presenting cells

2019 ◽  
Author(s):  
Alison Taylor ◽  
Christopher E. Rudd
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Motility ◽  
Glycogen Synthase ◽  
Antigen Presenting Cells ◽  
Glycogen Synthase Kinase ◽  
Glycogen Synthase Kinase 3 ◽  
Serine Kinase ◽  
Multiple Substrates ◽  
Antigen Presenting

Abstract Objective: The threonine/serine kinase glycogen synthase kinase 3 (GSK-3) targets multiple substrates in T-cells, regulating the expression of Tbet and PD-1 on T-cells. However, it has been unclear whether GSK-3 can affect the motility of T-cells and their interactions with antigen presenting cells. Results: Here, we show that GSK-3 can regulate T-cell motility. Inhibition of GSK-3, by small molecule SB415286, reduced T-cell motility in terms of distance and displacement. Although SB415286 reduced the number of contacts, the dwell times of established contacts did not differ between T-cells treated with SB415286. These data indicate show that the inhibition of GSK-3 can influence the motility of T-cells and interactions with other cells without affecting the dwell times of cells that make productive contacts.

scholarly journals Glycogen synthase kinase 3 (GSK-3) controls T-cell motility and interactions with antigen presenting cells

2019 ◽  
Author(s):  
Alison Taylor ◽  
Christopher E. Rudd
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Motility ◽  
Glycogen Synthase ◽  
Antigen Presenting Cells ◽  
Glycogen Synthase Kinase ◽  
Glycogen Synthase Kinase 3 ◽  
Serine Kinase ◽  
Multiple Substrates ◽  
Antigen Presenting

Abstract Objective: The threonine/serine kinase glycogen synthase kinase 3 (GSK-3) targets multiple substrates in T-cells, regulating the expression of Tbet and PD-1 on T-cells. However, it has been unclear whether GSK-3 can affect the motility of T-cells and their interactions with antigen presenting cells. Results: Here, we show that GSK-3 can regulate T-cell motility. Inhibition of GSK-3, by small molecule SB415286, reduced T-cell motility in terms of distance and displacement. Although SB415286 reduced the number of contacts, the dwell times of established contacts did not differ between T-cells treated with SB415286. These data indicate show that the inhibition of GSK-3 can influence the motility of T-cells and interactions with other cells without affecting the dwell times of cells that make productive contacts.

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