scholarly journals Cdc42-interacting protein–4 functionally links actin and microtubule networks at the cytolytic NK cell immunological synapse

2007 ◽  
Vol 204 (10) ◽  
pp. 2305-2320 ◽  
Author(s):  
Pinaki P. Banerjee ◽  
Rahul Pandey ◽  
Rena Zheng ◽  
Megan M. Suhoski ◽  
Linda Monaco-Shawver ◽  
...  
Keyword(s):  
Actin Filament ◽  
Cell Activation ◽  
Immunological Synapse ◽  
Nk Cell ◽  
Filamentous Actin ◽  
Microtubule Organizing Center ◽  
Interacting Protein ◽  
Lytic Granules ◽  
Organizing Center ◽  
Microtubule Networks

An essential function of the immunological synapse (IS) is directed secretion. NK cells are especially adept at this activity, as they direct lytic granules to the synapse for secretion, which enables cytotoxicity and facilitates host defense. This initially requires rearrangement of the actin cytoskeleton and, subsequently, microtubule-dependent trafficking of the lytic granules. As these two steps are sequential, specific linkages between them are likely to serve as critical regulators of cytotoxicity. We studied Cdc42-interacting protein–4 (CIP4), which constitutively interacts with tubulin and microtubules but focuses to the microtubule organizing center (MTOC) after NK cell activation, when it is able to associate with Wiskott-Aldrich syndrome protein (WASp) and the actin filament–rich IS. WASp deficiency, overexpression of CIP4, or parts of CIP4 interfere with this union and block normal CIP4 localization, MTOC polarization to the IS, and cytotoxicity. Reduction of endogenous CIP4 expression using small interfering RNA similarly inhibits MTOC polarization and cytotoxic activity but does not impair actin filament accumulation at the IS, or Cdc42 activation. Thus, CIP4 is an important cytoskeletal adaptor that functions after filamentous actin accumulation and Cdc42 activation to enable MTOC polarization and NK cell cytotoxicity.

scholarly journals Cdc42-interacting protein–4 functionally links actin and microtubule networks at the cytolytic NK cell immunological synapse

2007 ◽  
Vol 178 (6) ◽  
pp. i13-i13 ◽  
Author(s):  
Pinaki P. Banerjee ◽  
Rahul Pandey ◽  
Rena Zheng ◽  
Megan M. Suhoski ◽  
Linda Monaco-Shawver ◽  
...  
Keyword(s):  
Immunological Synapse ◽  
Nk Cell ◽  
Interacting Protein ◽  
Microtubule Networks

scholarly journals Rap1b facilitates NK cell functions via IQGAP1-mediated signalosomes

2010 ◽  
Vol 207 (9) ◽  
pp. 1923-1938 ◽  
Author(s):  
Aradhana Awasthi ◽  
Asanga Samarakoon ◽  
Haiyan Chu ◽  
Rajasekaran Kamalakannan ◽  
Lawrence A. Quilliam ◽  
...  
Keyword(s):  
Nk Cells ◽  
Cell Activation ◽  
Synapse Formation ◽  
Nk Cell ◽  
Scaffolding Protein ◽  
Microtubule Organizing Center ◽  
Chemokine Production ◽  
Immune Synapse ◽  
Cell Functions ◽  
Organizing Center

Rap1 GTPases control immune synapse formation and signaling in lymphocytes. However, the precise molecular mechanism by which Rap1 regulates natural killer (NK) cell activation is not known. Using Rap1a or Rap1b knockout mice, we identify Rap1b as the major isoform in NK cells. Its absence significantly impaired LFA1 polarization, spreading, and microtubule organizing center (MTOC) formation in NK cells. Neither Rap1 isoform was essential for NK cytotoxicity. However, absence of Rap1b impaired NKG2D, Ly49D, and NCR1-mediated cytokine and chemokine production. Upon activation, Rap1b colocalized with the scaffolding protein IQGAP1. This interaction facilitated sequential phosphorylation of B-Raf, C-Raf, and ERK1/2 and helped IQGAP1 to form a large signalosome in the perinuclear region. These results reveal a previously unrecognized role for Rap1b in NK cell signaling and effector functions.

scholarly journals NK cells converge lytic granules to promote cytotoxicity and prevent bystander killing

2016 ◽  
Vol 215 (6) ◽  
pp. 875-889 ◽  
Author(s):  
Hsiang-Ting Hsu ◽  
Emily M. Mace ◽  
Alexandre F. Carisey ◽  
Dixita I. Viswanath ◽  
Athanasia E. Christakou ◽  
...  
Keyword(s):  
Nk Cells ◽  
Cell Activation ◽  
Nk Cell ◽  
Cell Cytotoxicity ◽  
Microtubule Organizing Center ◽  
Lytic Granules ◽  
Nk Cell Cytotoxicity ◽  
Bystander Killing ◽  
Lysosome Related Organelles ◽  
The Impact

Natural killer (NK) cell activation triggers sequential cellular events leading to destruction of diseased cells. We previously identified lytic granule convergence, a dynein- and integrin signal–dependent movement of lysosome-related organelles to the microtubule-organizing center, as an early step in the cell biological process underlying NK cell cytotoxicity. Why lytic granules converge during NK cell cytotoxicity, however, remains unclear. We experimentally controlled the availability of human ligands to regulate NK cell signaling and promote granule convergence with either directed or nondirected degranulation. By the use of acoustic trap microscopy, we generated specific effector–target cell arrangements to define the impact of the two modes of degranulation. NK cells with converged granules had greater targeted and less nonspecific “bystander” killing. Additionally, NK cells in which dynein was inhibited or integrin blocked under physiological conditions demonstrated increased nondirected degranulation and bystander killing. Thus, NK cells converge lytic granules and thereby improve the efficiency of targeted killing and prevent collateral damage to neighboring healthy cells.

Rituximab causes a polarization of B cells that augments its therapeutic function in NK-cell–mediated antibody-dependent cellular cytotoxicity

Blood ◽  
2013 ◽  
Vol 121 (23) ◽  
pp. 4694-4702 ◽  
Author(s):  
Dominika Rudnicka ◽  
Anna Oszmiana ◽  
Donna K. Finch ◽  
Ian Strickland ◽  
Darren J. Schofield ◽  
...  
Keyword(s):  
B Cells ◽  
Nk Cell ◽  
Intercellular Adhesion Molecule ◽  
Cellular Cytotoxicity ◽  
Antibody Dependent Cellular Cytotoxicity ◽  
Intercellular Adhesion Molecule 1 ◽  
Microtubule Organizing Center ◽  
Key Points ◽  
Therapeutic Function ◽  
Organizing Center

Key Points Rituximab causes a polarization of B cells, involving a reorganization of CD20, intercellular adhesion molecule 1, and moesin, and orientation of the microtubule organizing center. The polarization of B cells induced by rituximab augments its therapeutic role in triggering ADCC by effector NK cells.

scholarly journals Reorganization of actin filaments by ADF/cofilin is involved in formation of microtubule structures during Xenopus oocyte maturation

2015 ◽  
Vol 26 (24) ◽  
pp. 4387-4400 ◽  
Author(s):  
Yuka Yamagishi ◽  
Hiroshi Abe
Keyword(s):  
Oocyte Maturation ◽  
Actin Filament ◽  
Actin Filaments ◽  
Xenopus Oocyte ◽  
Germinal Vesicle ◽  
Meiotic Spindle ◽  
Base Region ◽  
Microtubule Organizing Center ◽  
Cytoplasmic Actin ◽  
Organizing Center

We examined the reorganization of actin filaments and microtubules during Xenopus oocyte maturation. Surrounding the germinal vesicle (GV) in immature oocytes, the cytoplasmic actin filaments reorganized to accumulate beneath the vegetal side of the GV, where the microtubule-organizing center and transient microtubule array (MTOC-TMA) assembled, just before GV breakdown (GVBD). Immediately after GVBD, both Xenopus ADF/cofilin (XAC) and its phosphatase Slingshot (XSSH) accumulated into the nuclei and intranuclear actin filaments disassembled from the vegetal side with the shrinkage of the GV. As the MTOC-TMA developed well, cytoplasmic actin filaments were retained at the MTOC-TMA base region. Suppression of XAC dephosphorylation by anti-XSSH antibody injection inhibited both actin filament reorganization and proper formation and localization of both the MTOC-TMA and meiotic spindles. Stabilization of actin filaments by phalloidin also inhibited formation of the MTOC-TMA and disassembly of intranuclear actin filaments without affecting nuclear shrinkage. Nocodazole also caused the MTOC-TMA and the cytoplasmic actin filaments at its base region to disappear, which further impeded disassembly of intranuclear actin filaments from the vegetal side. XAC appears to reorganize cytoplasmic actin filaments required for precise assembly of the MTOC and, together with the MTOC-TMA, regulate the intranuclear actin filament disassembly essential for meiotic spindle formation.

scholarly journals Stochastic model of T Cell repolarization during target elimination (II)

2021 ◽  
Author(s):  
Ivan Hornak ◽  
Heiko Rieger
Keyword(s):  
T Cell ◽  
Immunological Synapse ◽  
Molecular Motor ◽  
Initial Position ◽  
Cell Polarization ◽  
Target Cells ◽  
Microtubule Organizing Center ◽  
Tight Contact ◽  
Organizing Center ◽  
Arbitrary Position

Cytotoxic T lymphocytes (T cells) and natural killer cells form a tight contact, the immunological synapse (IS), with target cells, where they release their lytic granules containing perforin/granzyme and cytokine containing vesicles. During this process the cell repolarizes and moves the microtubule organizing center (MTOC) towards the IS. In the first part of our work we developed a computational model for the molecular-motor-driven motion of the MT cytoskeleton confined between plasma membrane and nucleus during T cell polarization and analyzed different mechanisms (cortical sliding and capture-shrinkage) that have been proposed on the basis of recent experiments. Here we use this model to analyze the dynamics of the MTOC during the repositioning process in situations in which a) the IS is in an arbitrary position with respect to the initial position of the MTOC and b) the T cell has two IS at two arbitrary positions. We observe several scenarios that have also been reported experimentally: the MTOC alternates stochastically (but with a well defined average transition time) between the two IS; it wiggles in between the two IS without transiting to one of the two; or it is at some point pulled to one of the two IS and stays there. Our model allows to predict which scenario emerges in dependency of the mechanisms in action and the number of dyneins present.

scholarly journals Dendritic cell-expressed common gamma-chain recruits IL-15 for trans-presentation at the murine immunological synapse

2018 ◽  
Vol 3 ◽  
pp. 84 ◽  
Author(s):  
Chiara Beilin ◽  
Kaushik Choudhuri ◽  
Gerben Bouma ◽  
Dessislava Malinova ◽  
Jaime Llodra ◽  
...  
Keyword(s):  
T Cell ◽  
Dendritic Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Immunological Synapse ◽  
Nk Cell ◽  
Severe Combined Immunodeficiency ◽  
Cd4 T Cell ◽  
Gamma Chain

Background:Mutations of the common cytokine receptor gamma chain (γc) cause Severe Combined Immunodeficiency characterized by absent T and NK cell development. Although stem cell therapy restores these lineages, residual immune defects are observed that may result from selective persistence of γc-deficiency in myeloid lineages. However, little is known about the contribution of myeloid-expressed γc to protective immune responses.  Here we examine the importance of γc for myeloid dendritic cell (DC) function.Methods:We utilize a combination ofin vitroDC/T-cell co-culture assays and a novel lipid bilayer system mimicking the T cell surface to delineate the role of DC-expressed γc during DC/T-cell interaction.Results:We observed that γc in DC was recruited to the contact interface following MHCII ligation, and promoted IL-15Rα colocalization with engaged MHCII. Unexpectedly, trans-presentation of IL-15 was required for optimal CD4+T cell activation by DC and depended on DC γc expression. Neither recruitment of IL-15Rα nor IL-15 trans-signaling at the DC immune synapse (IS), required γc signaling in DC, suggesting that γc facilitates IL-15 transpresentation through induced intermolecularcisassociations or cytoskeletal reorganization following MHCII ligation.Conclusions:These findings show that DC-expressed γc is required for effective antigen-induced CD4+ T cell activation. We reveal a novel mechanism for recruitment of DC IL-15/IL-15Rα complexes to the IS, leading to CD4+ T cell costimulation through localized IL-15 transpresentation that is coordinated with antigen-recognition.

scholarly journals Interplay Between SNX27 and DAG Metabolism in the Control of Trafficking and Signaling at the IS

2020 ◽  
Vol 21 (12) ◽  
pp. 4254
Author(s):  
Natalia González-Mancha ◽  
Isabel Mérida
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Cell Communication ◽  
Negative Regulator ◽  
Cell Junction ◽  
Microtubule Organizing Center ◽  
Immune Synapse ◽  
Organizing Center ◽  
Cell Cell

Recognition of antigens displayed on the surface of an antigen-presenting cell (APC) by T-cell receptors (TCR) of a T lymphocyte leads to the formation of a specialized contact between both cells named the immune synapse (IS). This highly organized structure ensures cell–cell communication and sustained T-cell activation. An essential lipid regulating T-cell activation is diacylglycerol (DAG), which accumulates at the cell–cell interface and mediates recruitment and activation of proteins involved in signaling and polarization. Formation of the IS requires rearrangement of the cytoskeleton, translocation of the microtubule-organizing center (MTOC) and vesicular compartments, and reorganization of signaling and adhesion molecules within the cell–cell junction. Among the multiple players involved in this polarized intracellular trafficking, we find sorting nexin 27 (SNX27). This protein translocates to the T cell–APC interface upon TCR activation, and it is suggested to facilitate the transport of cargoes toward this structure. Furthermore, its interaction with diacylglycerol kinase ζ (DGKζ), a negative regulator of DAG, sustains the precise modulation of this lipid and, thus, facilitates IS organization and signaling. Here, we review the role of SNX27, DAG metabolism, and their interplay in the control of T-cell activation and establishment of the IS.

Sign in / Sign up

Export Citation Format

Share Document