scholarly journals Cytoskeletal Polarization of T Cells Is Regulated by an Immunoreceptor Tyrosine-based Activation Motif–dependent Mechanism

1998 ◽  
Vol 140 (4) ◽  
pp. 861-871 ◽  
Author(s):  
Bente Lowin-Kropf ◽  
Virginia Smith Shapiro ◽  
Arthur Weiss
Keyword(s):  
T Cells ◽  
T Cell ◽  
Actin Polymerization ◽  
Gene Activation ◽  
Attachment Site ◽  
Cell Polarization ◽  
Cell Contact ◽  
Microtubule Organizing Center ◽  
T Cell Polarization ◽  
Cytoskeletal Rearrangements

Abstract. Binding of a T cell to an appropriate antigen-presenting cell (APC) induces the rapid reorientation of the T cell cytoskeleton and secretory apparatus towards the cell–cell contact site in a T cell antigen receptor (TCR) and peptide/major histocompatibility complex–dependent process. Such T cell polarization directs the delivery of cytokines and cytotoxic mediators towards the APC and contributes to the highly selective and specific action of effector T cells. To study the signaling pathways that regulate cytoskeletal rearrangements in T lymphocytes, we set up a conjugate formation assay using Jurkat T cells as effectors and cell-sized latex beads coated with various antibodies as artificial APCs. Here, we report that beads coated with antibodies specific for the TCR-CD3 complex were sufficient to induce T cell polarization towards the bead attachment site, as judged by reorientation of the microtubule-organizing center (MTOC) and localized actin polymerization. Thus, these cytoskeletal changes did not depend on activation of additional coreceptors. Moreover, single subunits of the TCR complex, namely TCR-ζ and CD3ε, were equally effective in inducing cytoskeletal polarization. However, mutagenesis of the immunoreceptor tyrosine-based activation motifs (ITAMs), present three times in TCR-ζ and once in CD3ε, revealed that the induction of cytoskeletal rearrangements required the presence of at least one intact ITAM. In agreement with this result, lack of functional Lck, the protein tyrosine kinase responsible for ITAM phosphorylation, abolished both MTOC reorientation and polarized actin polymerization. Both inhibitor and transient overexpression studies demonstrated that MTOC reorientation could occur in the absence of Ras activation. Our results suggest that APC-induced T cell polarization is a TCR-mediated event that is coupled to the TCR by the same signaling motif as TCR-induced gene activation, but diverges in its distal signaling requirements.

scholarly journals Leptin: A Critical Regulator of CD4+ T-cell Polarization in Vitro and in Vivo

Endocrinology ◽  
2010 ◽  
Vol 151 (1) ◽  
pp. 56-62 ◽  
Author(s):  
Arvind Batra ◽  
Besir Okur ◽  
Rainer Glauben ◽  
Ulrike Erben ◽  
Jakob Ihbe ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Polarization ◽  
Th2 Cells ◽  
Regulatory Function ◽  
Wild Type ◽  
T Helper ◽  
T Cell Polarization

Abstract Besides being mandatory in the metabolic system, adipokines like leptin directly affect immunity. Leptin was found to be necessary in T helper 1 (Th1)-dependent inflammatory processes, whereas effects on Th2 cells are rarely understood. Here, we focused on leptin in T-helper cell polarization and in Th2-mediated intestinal inflammation in vivo. The induction of cytokine-producing Th1 or Th2 cells from naive CD4+ T cells under polarizing conditions in vitro was generally decreased in cells from leptin-deficient ob/ob mice compared with wild-type mice. To explore the in vivo relevance of leptin in Th2-mediated inflammation, the model of oxazolone-induced colitis was employed in wild-type, ob/ob, and leptin-reconstituted ob/ob mice. Ob/ob mice were protected, whereas wild-type and leptin-reconstituted ob/ob mice developed colitis. The disease severity went in parallel with local production of the Th2 cytokine IL-13. A possible explanation for the protection of ob/ob mice in Th1- as well as in Th2-dependent inflammation is provided by a decreased expression of the key transcription factors for Th1 and Th2 polarization, T-bet and GATA-3, in naive ob/ob T cells. In conclusion, these results support the regulatory function of the adipokine leptin within T-cell polarization and thus in the acquired immune system and support the concept that there is a close interaction with the endocrine system.

scholarly journals Interleukin-23 deficiency alters thymic selection in lupus-prone mice

Lupus ◽  
2019 ◽  
Vol 28 (8) ◽  
pp. 1007-1012
Author(s):  
H Dai ◽  
V C Kyttaris
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Polarization ◽  
Lymphoid Organs ◽  
Thymic Selection ◽  
Wild Type ◽  
Thymic Development ◽  
T Cell Polarization ◽  
Interleukin 23 ◽  
Secondary Lymphoid Organs

We have previously reported that IL-23 receptor deficiency in MRL. lpr mice ameliorates lupus by altering the balance of pro- and anti-inflammatory cytokines in secondary lymphoid organs. As IL-23 may also impact thymic selection, we evaluated the effect of IL-23 on thymic T cell development in lupus-prone mice. We generated IL-23p19-deficient MRL. lpr mice and harvested their thymus at 8 weeks of age. We found that the late stage double negative DN4 population was increased in IL-23p19–/– MRL. lpr mice when compared to IL-23p19+/+ MRL. lpr mice. Despite this, mature thymocytes (CD24–TCRβ+) were decreased by more than 50% in the IL-23p19-deficient mice versus wild-type controls. This was associated with a decrease in the generation of CD8+ T cells, possibly through downregulation of the IL-7 receptor. CD8+ T cells were not only fewer in numbers but also had decreased expression of the migration-related receptors CD44 and CD62L in the thymus and spleens of IL-23p19-deficient versus wild-type mice. We propose that IL-23 promotes the development of lupus-like autoimmunity not only through T cell polarization and cytokine production in the peripheral lymphoid organs but also by influencing T cell thymic development.

scholarly journals The Par polarity complex regulates Rap1- and chemokine-induced T cell polarization

2007 ◽  
Vol 176 (6) ◽  
pp. 863-875 ◽  
Author(s):  
Audrey Gérard ◽  
Alexander E.E. Mertens ◽  
Rob A. van der Kammen ◽  
John G. Collard
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Polarity ◽  
Intracellular Localization ◽  
Transendothelial Migration ◽  
Induced Polarization ◽  
Cell Polarization ◽  
Molecular Pathways ◽  
T Cell Polarization ◽  
Actin Remodelling

Cell polarization is required for virtually all functions of T cells, including transendothelial migration in response to chemokines. However, the molecular pathways that establish T cell polarity are poorly understood. We show that the activation of the partitioning defective (Par) polarity complex is a key event during Rap1- and chemokine-induced T cell polarization. Intracellular localization and activation of the Par complex are initiated by Rap1 and require Cdc42 activity. The Rac activator Tiam1 associates with both Rap1 and components of the Par complex, and thereby may function to connect the Par polarity complex to Rap1 and to regulate the Rac-mediated actin remodelling required for T cell polarization. Consistent with these findings, Tiam1-deficient T cells are impaired in Rap1- and chemokine-induced polarization and chemotaxis. Our studies implicate Tiam1 and the Par polarity complex in polarization of T cells, and provide a mechanism by which chemokines and Rap1 regulate T cell polarization and chemotaxis.

scholarly journals The specific direct interaction of helper T cells and antigen-presenting B cells. II. Reorientation of the microtubule organizing center and reorganization of the membrane-associated cytoskeleton inside the bound helper T cells.

1987 ◽  
Vol 165 (6) ◽  
pp. 1565-1580 ◽  
Author(s):  
A Kupfer ◽  
S L Swain ◽  
S J Singer
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cell ◽  
Direct Interaction ◽  
Helper T Cells ◽  
Hybridoma Cells ◽  
Cell Contact ◽  
Specific Cell ◽  
Microtubule Organizing Center ◽  
Th Cell

We have produced and investigated cell couples formed between cloned Th cells or T hybridoma cells, and either Ag-presenting B hybridoma or B lymphoma cells. The specific direct interaction between a Th and B-APC is here demonstrated by two rearrangements occurring inside the bound Th cell; the MTOC (and presumably the GA) is oriented to face the cell contact region with the B cell, and a membrane-associated cytoskeletal protein, talin, becomes concentrated under the contacting Th membrane. In the absence of the specific Ag or the correct Ia determinant, nonspecific T-B cell couples form that are morphologically indistinguishable from specific cell couples in the light microscope, but neither the MTOC nor the talin rearrangement occurs inside the bound T cell of such nonspecific couples. Furthermore, Ag processing by the B cell is required to produce the MTOC and talin rearrangements within the T cell in specific T-B couples. In the case of allogeneic Th-B cell couples, similar specific MTOC and talin rearrangements are observed inside the Th. Extracellular Ca2+ is required for the MTOC orientation to occur inside the specifically bound Th cell, but not for the talin rearrangement. It is proposed that the MTOC (and GA) reorientation and the talin rearrangement are involved in the directed secretion of GA-derived lymphokines from the Th cell to the bound B cell.

scholarly journals Kinesin-4 KIF21B limits microtubule growth to allow rapid centrosome polarization in T cells

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Peter Jan Hooikaas ◽  
Hugo GJ Damstra ◽  
Oane J Gros ◽  
Wilhelmina E van Riel ◽  
Maud Martin ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immunological Synapse ◽  
Cell Polarization ◽  
Contact Site ◽  
Cell Form ◽  
Pulling Forces ◽  
T Cell Polarization ◽  
Microtubule Growth ◽  
Antigen Presenting

When a T cell and an antigen-presenting cell form an immunological synapse, rapid dynein-driven translocation of the centrosome towards the contact site leads to reorganization of microtubules and associated organelles. Currently, little is known about how the regulation of microtubule dynamics contributes to this process. Here, we show that the knockout of KIF21B, a kinesin-4 linked to autoimmune disorders, causes microtubule overgrowth and perturbs centrosome translocation. KIF21B restricts microtubule length by inducing microtubule pausing typically followed by catastrophe. Catastrophe induction with vinblastine prevented microtubule overgrowth and was sufficient to rescue centrosome polarization in KIF21B-knockout cells. Biophysical simulations showed that a relatively small number of KIF21B molecules can restrict microtubule length and promote an imbalance of dynein-mediated pulling forces that allows the centrosome to translocate past the nucleus. We conclude that proper control of microtubule length is important for allowing rapid remodeling of the cytoskeleton and efficient T cell polarization.

scholarly journals Fructo-Oligosaccharides Modify Human DC Maturation and Peanut-Induced Autologous T-Cell Response of Allergic Patients In Vitro

2021 ◽  
Vol 11 ◽  
Author(s):  
Simone M. Hayen ◽  
André C. Knulst ◽  
Johan Garssen ◽  
Henny G. Otten ◽  
Linette E. M. Willemsen
Keyword(s):  
T Cells ◽  
T Cell ◽  
Antigen Presentation ◽  
Cell Response ◽  
Cell Polarization ◽  
T Cell Response ◽  
Th2 Cells ◽  
Cell Assay ◽  
T Cell Polarization ◽  
Dc Maturation

BackgroundDendritic cells (DCs) play an important role in antigen presentation, and are an interesting target for immune-modulation in allergies. Short- and long-chain fructo-oligosaccharides (scFOS/lcFOS, FF) have immunomodulatory capacities, and may influence the outcome of DC antigen presentation.ObjectiveThis study investigated the effect of FF during DC maturation and allergen presentation using cells of peanut-allergic patients in an autologous DC-T cell assay.MethodsCD14+ and CD4+ T cells were isolated from peanut-allergic patients. CD14+ monocytes were differentiated into immature DCs (imDCs), and matured (matDCs) in the presence or absence of crude peanut-extract (CPE) and/or FF, and co-cultured in an autologous DC-T cell assay. T cell polarization, proliferation and cytokine production were measured.ResultsExpression of maturation surface molecule markers on matDCs was not affected by CPE and/or FF. By contrast, the IL-10 secretion by matDCs increased compared to imDCs, upon exposure to CPE and FF compared to CPE alone. Also the IP-10 secretion increased in CPE/FF-matDCs compared to imDC. CPE-matDCs enhanced IL-13 release in the DC-T-cell assay and Treg polarization in presence or absence of FF. CPE/FF-DCs tended to increase the Treg/Th1 and Treg/Th2 ratios compared to matDCs. The proliferation of both Treg and Th2 cells tended to increase when T cells were co-cultured with CPE-matDCs compared to matDCs, which became significant when CPE-matDCs were also exposed to FF and a same tendency was shown for Th1 proliferation.ConclusionOnly in the presence of FF, CPE-matDCs produced increased regulatory and Th1-related mediators. CPE-matDCs modified T cell polarization and proliferation, and additional exposure to FF tended to enhance Treg/Th2 and Treg/Th1 ratios instructed by CPE/FF-matDCs. However this effect was not strong enough to suppress CPE-matDCs induced IL-13 release by Th-cells. This indicates the ability of FF to modify DC maturation in the presence of an allergen supporting a more Treg/Th1 prone direction of the successive allergen specific Th2 cell response.

scholarly journals LFA-1 Engagement Triggers T Cell Polarization at the HIV-1 Virological Synapse

2016 ◽  
Vol 90 (21) ◽  
pp. 9841-9854 ◽  
Author(s):  
Shimona Starling ◽  
Clare Jolly
Keyword(s):  
T Cell ◽  
Cell Polarization ◽  
Cell Contact ◽  
Cell Remodeling ◽  
T Cell Polarization ◽  
Infected Cells ◽  
Virological Synapses ◽  
Cell Spread ◽  
Hiv 1 ◽  
Cell Cell

ABSTRACTHIV-1 efficiently disseminates by cell-cell spread at intercellular contacts called virological synapses (VS), where the virus preferentially assembles and buds. Cell-cell contact triggers active polarization of organelles and viral proteins within infected cells to the contact site to support efficient VS formation and HIV-1 spread; critically, however, which cell surface protein triggers contact-induced polarization at the VS remains unclear. Additionally, the mechanism by which the HIV-1 envelope glycoprotein (Env) is recruited to the VS remains ill defined. Here, we use a reductionist bead-coupled antibody assay as a model of the VS and show that cross-linking the integrin LFA-1 alone is sufficient to induce active T cell polarization and recruitment of the microtubule organizing center (MTOC) in HIV-1-infected cells. Mutant cell lines coupled with inhibitors demonstrated that LFA-1-induced polarization was dependent on the T cell kinase ZAP70. Notably, immunofluorescent staining of viral proteins revealed an accumulation of surface Env at sites of LFA-1 engagement, with intracellular Env localized to a Golgi compartment proximal to the polarized MTOC. Furthermore, blocking LFA-1-induced MTOC polarization through ZAP70 inhibition prevented intracellular Env polarization. Taken together, these data reveal that LFA-1 is a key determinant in inducing dynamic T cell remodeling to the VS and suggest a model in which LFA-1 engagement triggers active polarization of the MTOC and the associated Env-containing secretory apparatus to sites of cell-cell contact to support polarized viral assembly and egress for efficient cell-cell spread.IMPORTANCEHIV-1 causes AIDS by spreading within immune cells and depletion of CD4 T lymphocytes. Rapid spread between these cells occurs by highly efficient cell-cell transmission that takes place at virological synapses (VS). VS are characterized by striking T cell remodeling that is spatially associated with polarized virus assembly and budding at sites of cell contact. Here, we show that the integrin LFA-1 triggers organelle polarization and viral protein recruitment, facilitating formation of the VS, and that this requires the T cell kinase ZAP70. Taken together, these data suggest a mechanism by which HIV-1-infected T cells sense and respond to cell contact to polarize viral egress and promote cell-cell spread. Understanding how cell-cell spread is regulated may help reveal therapeutic targets to specifically block this mode of HIV-1 dissemination.

scholarly journals Kinesin-4 KIF21B limits microtubule growth to allow rapid centrosome polarization in T cells

2020 ◽  
Author(s):  
Peter Jan Hooikaas ◽  
Hugo G.J. Damstra ◽  
Oane J. Gros ◽  
Wilhelmina E. van Riel ◽  
Maud Martin ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immunological Synapse ◽  
Cell Polarization ◽  
Contact Site ◽  
Cell Form ◽  
Pulling Forces ◽  
T Cell Polarization ◽  
Microtubule Growth ◽  
Antigen Presenting

AbstractWhen a T cell and an antigen-presenting cell form an immunological synapse, rapid dynein-driven translocation of the centrosome towards the contact site leads to reorganization of microtubules and associated organelles. Currently, little is known about how the regulation of microtubule dynamics contributes to this process. Here, we show that the knockout of KIF21B, a kinesin-4 linked to autoimmune disorders, causes microtubule overgrowth and perturbs centrosome translocation. KIF21B restricts microtubule length by inducing microtubule pausing typically followed by catastrophe. Catastrophe induction with vinblastine prevented microtubule overgrowth and was sufficient to rescue centrosome polarization in KIF21B-knockout cells. Biophysical simulations showed that a relatively small number of KIF21B molecules can restrict microtubule length and promote an imbalance of dynein-mediated pulling forces that allows the centrosome to translocate past the nucleus. We conclude that proper control of microtubule length is important for allowing rapid remodeling of the cytoskeleton and efficient T cell polarization.

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