bluuebunny/crossref_metadata_2025_split huggingface dataset:
The actin‐bundling protein L‐plastin supports T‐cell motility and activation
Authors: Morley Sharon Celeste 
Published: August 2014

SummaryTight regulation of actin dynamics is essential for T‐cell trafficking and activation. Recent studies in human and murine T cells reveal that T‐cell motility and full T‐cell activation require the hematopoietic‐specific, actin‐bundling protein L‐plastin (LPL). T cells lackingLPLdo not form fully mature synapses and thus demonstrate reduced cytokine production and proliferation. Reduction or loss ofLPLexpression also reduces the velocity of T cells and impairs thymic egress and intranodal motility. Whereas dispensable for proximal T‐cell receptor and chemokine receptor signaling,LPLis critical to the later stages of synapse maturation and cellular polarization. Serine phosphorylation, calcium, and calmodulin binding regulate the bundling activity and localization ofLPLfollowing T‐cell receptor and chemokine receptor engagement. However, the interaction between these regulatory domains and resulting changes in local control of actin cytoskeletal structures has not been fully elucidated. Circumstantial evidence suggests a function forLPLin either the formation or maintenance of integrin‐associated adhesion structures. AsLPLmay be a target of the commonly used immunosuppressive agent dexamethasone, full elucidation of the regulation and function ofLPLin T‐cell biology may illuminate new pathways for clinically useful immunotherapeutics.
The actin‐driven spatiotemporal organization of T‐cell signaling at the system scale
Authors: Roybal Kole T. , Sinai Parisa , Verkade Paul , Murphy Robert F. , Wülfing Christoph 
Published: August 2014

SummaryT cells are activated through interaction with antigen‐presenting cells (APCs). During activation, receptors and signaling intermediates accumulate in diverse spatiotemporal distributions. These distributions control the probability of signaling interactions and thus govern information flow through the signaling system. Spatiotemporally resolved system‐scale investigation of signaling can extract the regulatory information thus encoded, allowing unique insight into the control of T‐cell function. Substantial technical challenges exist, and these are briefly discussed herein. While much of the work assessing T‐cell spatiotemporal organization uses planar APC substitutes, we focus here on B‐cell APCs with often stark differences. Spatiotemporal signaling distributions are driven by cell biologically distinct structures, a large protein assembly at the interface center, a large invagination, the actin‐supported interface periphery as extended by smaller individual lamella, and a newly discovered whole‐interface actin‐driven lamellum. The more than 60 elements of T‐cell activation studied to date are dynamically distributed between these structures, generating a complex organization of the signaling system. Signal initiation and core signaling prefer the interface center, while signal amplification is localized in the transient lamellum. Actin dynamics control signaling distributions through regulation of the underlying structures and drive a highly undulating T‐cell/APC interface that imposes substantial constraints on T‐cell organization. We suggest that the regulation of actin dynamics, by controlling signaling distributions and membrane topology, is an important rheostat of T‐cell signaling.
Re‐defining ERM function in lymphocyte activation and migration
Authors: Parameswaran Neetha , Gupta Neetu 
Published: August 2014

SummaryLymphocyte activation and migration involve large‐scale actin cytoskeletal remodeling. The Ezrin–Radixin–Moesin (ERM) family proteins reversibly link the plasma membrane and cortical actin meshwork and mediate the dynamic nature of the membrane‐cytoskeletal interface to facilitate remodeling. The reversibility of this linkage is controlled by the conformation of ERM proteins and depends on the phosphorylation of a conserved threonine residue in the actin‐binding domain. Disruption of the phospho‐cycling nature of ERM proteins through dominant negative and constitutively active mutants results in impaired lymphocyte migration and activation. In recent years, a novel role has emerged for ERM proteins as signaling scaffolds that can modulate B and T‐cell activation through additional posttranslational modifications at tyrosine residues. Here, we highlight recent studies that have redefined the role of ERM proteins in lymphocyte activation and migration. We discuss how lymphocyte‐specific knockouts of ERM proteins and high resolution imaging techniques have identified a novel function for them as rheostats that modulate the strength of antigen receptor signaling in B cells. Finally, we describe scenarios in which ERM protein function is coopted by pathogens for their own transmission and speculate on the potential of ERM proteins for regulating undesirable lymphocyte behaviors such as autoimmunity and malignancy.
Class I myosins in B‐cell physiology: functions in spreading, immune synapses, motility, and vesicular traffic
Authors: Santos‐Argumedo Leopoldo , Maravillas‐Montero José Luis , López‐Ortega Orestes 
Published: August 2014

SummaryMyosins comprise a family of motor proteins whose role in muscle contraction and motility in a large range of eukaryotic cells has been widely studied. Although these proteins have been characterized extensively and much is known about their function in different cellular compartments, little is known about these molecules in hematopoietic cells. Myosins expressed by cells from the immune response are involved in maintaining plasma membrane tension, moving and secreting vesicles, endo‐ and exocytotic processes, and promoting the adhesion and motility of cells. Herein, we summarize our current understanding of class I myosins in B cells, with an emphasis on the emerging roles of these molecular motors in immune functions.
Novel anti‐HIV therapeutics targeting chemokine receptors and actin regulatory pathways
Authors: Spear Mark , Guo Jia , Wu Yuntao 
Published: August 2014

SummaryThe human immunodeficiency virus‐1 (HIV‐1) infects helper CD4+ T cells, and causes CD4+ T‐cell depletion and immunodeficiency. In the past 30 years, significant progress has been made in antiretroviral therapy, and the disease has become manageable. Nevertheless, an effective vaccine is still nowhere in sight, and a cure or a functional cure awaits discovery. Among possible curative therapies, traditional antiretroviral therapy, mostly targeting viral proteins, has been proven ineffective. It is possible that targeting HIV‐dependent host cofactors may offer alternatives, both for preventing HIV transmission and for forestalling disease progression. Recently, the actin cytoskeleton and its regulators in blood CD4+ T cells have emerged as major host cofactors that could be targeted. The novel concept that the cortical actin is a barrier to viral entry and early post‐entry migration has led to the nascent model of virus‐host interaction at the cortical actin layer. Deciphering the cellular regulatory pathways has manifested exciting prospects for future therapeutics. In this review, we describe the study of HIV interactions with actin cytoskeleton. We also examine potential pharmacological targets that emerge from this interaction. In addition, we briefly discuss several actin pathway‐based anti‐HIV drugs that are currently in development or testing.
The central role of the cytoskeleton in mechanisms and functions of the NK cell immune synapse
Authors: Lagrue Kathryn , Carisey Alex , Oszmiana Anna , Kennedy Philippa R. , Williamson David J. , Cartwright Adam , Barthen Charlotte , Davis Daniel M. 
Published: August 2014

SummaryNatural killer (NK) cells discriminate between healthy and unhealthy target cells through a balance of activating and inhibitory signals at direct intercellular contacts called immune synapses. Rearrangements in the cellular cytoskeleton have long been known to be critical in assembly of immune synapses. Here, through bringing together the vast literature on this subject, the number of different ways in which the cytoskeleton is important becomes evident. The dynamics of filamentous actin are critical in (i) creating the nanometer‐scale organization of NK cell receptors, (ii) establishing cellular polarity, (iii) coordinating immune receptor and integrin‐mediated signaling, and (iv) directing secretion of lytic granules and cytokines. The microtubule network also is important in the delivery of lytic granules and vesicles containing cytokines to the immune synapse. Together, these data establish that the cytoskeleton acts as a central regulator of this complex and dynamic process – and an enormous amount of NK cell biology is controlled through the cytoskeleton.
Orchestrating cytoskeleton and intracellular vesicle traffic to build functional immunological synapses
Authors: Soares Helena , Lasserre Rémi , Alcover Andrés 
Published: August 2014

SummaryImmunological synapses are specialized cell–cell contacts formed between T lymphocytes and antigen‐presenting cells. They are induced upon antigen recognition and are crucial for T‐cell activation and effector functions. The generation and function of immunological synapses depend on an active T‐cell polarization process, which results from a finely orchestrated crosstalk between the antigen receptor signal transduction machinery, the actin and microtubule cytoskeletons, and controlled vesicle traffic. Although we understand how some of these particular events are regulated, we still lack knowledge on how these multiple cellular elements are harmonized to ensure appropriate T‐cell responses. We discuss here our view on how T‐cell receptor signal transduction initially commands cytoskeletal and vesicle traffic polarization, which in turn sets the immunological synapse molecular design that regulates T‐cell activation. We also discuss how the human immunodeficiency virus (HIV‐1) hijacks some of these processes impairing immunological synapse generation and function.
Actin‐mediated feedback loops in B‐cell receptor signaling
Authors: Song Wenxia , Liu Chaohong , Seeley‐Fallen Margaret K. , Miller Heather , Ketchum Christina , Upadhyaya Arpita 
Published: August 2014

SummaryUpon recognizing cognate antigen, B cells mobilize multiple cellular apparatuses to propagate an optimal response. Antigen binding is transduced into cytoplasmic signaling events through B‐cell antigen receptor (BCR)‐based signalosomes at the B‐cell surface. BCR signalosomes are dynamic and transient and are subsequently endocytosed for antigen processing. The function of BCR signalosomes is one of the determining factors for the fate of B cells: clonal expansion, anergy, or apoptosis. Accumulating evidence underscores the importance of the actin cytoskeleton in B‐cell activation. We have begun to appreciate the role of actin dynamics in regulating BCR‐mediated tonic signaling and the formation of BCR signalosomes. Our recent studies reveal an additional function of the actin cytoskeleton in the downregulation of BCR signaling, consequently contributing to the generation and maintenance of B‐cell self‐tolerance. In this review, we discuss how actin remodels its organization and dynamics in close coordination with BCR signaling and how actin remodeling in turn amplifies the activation and subsequent downregulation process of BCR signaling, providing vital feedback for optimal BCR activation.
Actin cytoskeletal defects in immunodeficiency
Authors: Moulding Dale A. , Record Julien , Malinova Dessislava , Thrasher Adrian J. 
Published: August 2014

SummaryThe importance of the cytoskeleton in mounting a successful immune response is evident from the wide range of defects that occur in actin‐related primary immunodeficiencies (PIDs). Studies of these PIDs have revealed a pivotal role for the actin cytoskeleton in almost all stages of immune system function, from hematopoiesis and immune cell development, through to recruitment, migration, intercellular and intracellular signaling, and activation of both innate and adaptive immune responses. The major focus of this review is the immune defects that result from mutations in the Wiskott‐Aldrich syndrome gene (WAS), which have a broad impact on many different processes and give rise to clinically heterogeneous immunodeficiencies. We also discuss other related genetic defects and the possibility of identifying new genetic causes of cytoskeletal immunodeficiency.
Cofilin: a redox sensitive mediator of actin dynamics during T‐cell activation and migration
Authors: Samstag Yvonne , John Isabel , Wabnitz Guido H. 
Published: August 2014

SummaryCofilin is an actin‐binding protein that depolymerizes and/or severs actin filaments. This dual function of cofilin makes it one of the major regulators of actin dynamics important for T‐cell activation and migration. The activity of cofilin is spatio‐temporally regulated. Its main control mechanisms comprise a molecular toolbox of phospho‐, phospholipid, and redox regulation. Phosphorylated cofilin is inactive and represents the dominant cofilin fraction in the cytoplasm of resting human T cells. A fraction of dephosphorylated cofilin is kept inactive at the plasma membrane by binding to phosphatidylinositol 4,5‐bisphosphate. Costimulation via the T‐cell receptor/CD3 complex (signal 1) together with accessory receptors (signal 2) or triggering through the chemokine SDF1α (stromal cell‐derived factor 1α) induce Ras‐dependent dephosphorylation of cofilin, which is important for immune synapse formation, T‐cell activation, and T‐cell migration. Recently, it became evident that cofilin is also highly sensitive for microenvironmental changes, particularly for alterations in the redox milieu. Cofilin is inactivated by oxidation, provoking T‐cell hyporesponsiveness or necrotic‐like programmed cell death. In contrast, in a reducing environment, even phosphatidylinositol 4,5‐bisphosphate ‐bound cofilin becomes active, leading to actin dynamics in the vicinity of the plasma membrane. In addition to the well‐established three signals for T‐cell activation, this microenvironmental control of cofilin delivers a modulating signal for T‐cell‐dependent immune reactions. This fourth modulating signal highly impacts both initial T‐cell activation and the effector phase of T‐cell‐mediated immune responses.
From lipid second messengers to molecular motors: microtubule‐organizing center reorientation in T cells
Authors: Huse Morgan , Le Floc'h Audrey , Liu Xin 
Published: August 2014

SummaryIn T lymphocytes, polarization of the microtubule‐organizing center (MTOC) to the immunological synapse enables the directional secretion of cytokines, cytolytic factors, and other soluble molecules toward the antigen‐presenting cell. This is likely to be crucial for maintaining the specificity of T‐cell effector responses. Here, we review recent advances in our understanding of MTOC reorientation in T cells, focusing first on the importance of diacylglycerol and protein kinase C isozymes and then on the molecular motor proteins that function downstream to drive MTOC movement.
The role of the cytoskeleton at the immunological synapse
Authors: Ritter Alex T. , Angus Karen L. , Griffiths Gillian M. 
Published: August 2014

SummaryIt has been over 30 years since the reorganization of both the microtubule network and a ‘peculiar actin polarization’ was reported at the contact area of cytotoxic T lymphocytes interacting with target cells. Since that time, hundreds of studies have been published in an effort to elucidate the structure and function of the microtubule network and the actin cytoskeleton in T‐cell activation, migration, and effector function at the interface between a T cell and its cognate antigen‐presenting cell or target cell. This interface has become known as the immunological synapse, and this review examines some of the roles played by the cytoskeleton at the synapse.
Generation of membrane structures during phagocytosis and chemotaxis of macrophages: role and regulation of the actin cytoskeleton
Authors: Rougerie Pablo , Miskolci Veronika , Cox Dianne 
Published: August 2014

SummaryMacrophages are best known for their protective search and destroy functions against invading microorganisms. These processes are commonly known as chemotaxis and phagocytosis. Both of these processes require actin cytoskeletal remodeling to produce distinct F‐actin‐rich membrane structures called lamellipodia and phagocytic cups. This review will focus on the mechanisms by which macrophages regulate actin polymerization through initial receptor signaling and subsequent Arp2/3 activation by nucleation‐promoting factors like the WASP/WAVE family, followed by remodeling of actin networks to produce these very distinct structures.
RhoGTPases control specific cytoskeleton‐dependent functions of hematopoietic stem cells
Authors: Nayak Ramesh C. , Chang Kyung‐Hee , Vaitinadin Nataraja‐Sarma , Cancelas Jose A. 
Published: August 2014

SummaryThe Rho family of guanosine triphosphatases (GTPases) is composed of members of the Ras superfamily of proteins. They areGTP‐bound molecules with a modest intrinsicGTPase activity that can be accelerated upon activation/localization of specialized guanine nucleotide exchange factors. Members of this family act as molecular switches and are required for coordinated cytoskeletal rearrangements that are crucial in a set of specialized functions of mammalian stem cells. These functions include self‐renewal, adhesion, and migration. Mouse gene‐targeting studies have provided convincing evidence of the indispensable and dispensable roles of individual members of the RhoGTPase family and the putative upstream and downstream mediators in stem cell‐specific functions. The role of RhoGTPases and related signaling pathways previously seen in other cell types and organisms have been confirmed in mammalian hematopoietic stem cells (HSCs), and new signaling pathways and unexpected functions unique toHSCs have been identified and dissected. This review summarizes our current understanding of the role of Rho family ofGTPases onHSCand progenitor activity through cytoskeleton‐mediated signaling pathways, providing insight about relevant signaling pathways that regulate mammalian stem cell self‐renewal, adhesion, and migration.
Regulation of T‐cell receptor signaling by the actin cytoskeleton and poroelastic cytoplasm
Authors: Beemiller Peter , Krummel Matthew F. 
Published: August 2014

SummaryThe actin cytoskeleton plays essential roles in modulating T‐cell activation. Most models of T‐cell receptor (TCR) triggering signalosome assembly and immune synapse formation invoke actin‐dependent mechanisms. As T cells are constitutively motile cells, TCR triggering and signaling occur against a cytoskeletal backdrop that is constantly remodeling. While the interplay between actin dynamics and TCR signaling have been the focus of research for many years, much of the work in T cells has considered actin largely for its ‘scaffolding’ function. We examine the roles of the actin cytoskeleton in TCR signaling and immune synapse formation with an emphasis on how poroelasticity, an ensemble feature of actin dynamics with the cytosol, relates to how T cells respond to stimulation.
Mechanical regulation of T‐cell functions
Authors: Chen Wei , Zhu Cheng 
Published: August 2014

SummaryT cells are key players of the mammalian adaptive immune system. They experience different mechanical microenvironments during their life cycle, from the thymus, secondary lymph organs, and peripheral tissues that are free of externally applied force, but display variable substrate rigidities to the blood and lymphatic circulation systems, where complicated hydrodynamic forces are present. Regardless of whether T cells are subject to external forces or generate their own internal forces, they respond and adapt to different biomechanical cues to modulate their adhesion, migration, trafficking, and triggering of immune functions through mechanical regulation of various molecules that bear force. These include adhesive receptors, immunoreceptors, motor proteins, cytoskeletal proteins, and their associated molecules. Here, we discuss the forces acting on various surface and cytoplasmic proteins of a T cell in different mechanical milieus. We review existing data on how force regulates protein conformational changes and interactions with counter molecules, including integrins, actin, and the T‐cell receptor, and how each relates to T‐cell functions.
Coordinate control of cytoskeletal remodeling and calcium mobilization during T‐cell activation
Authors: Babich Alexander , Burkhardt Janis K. 
Published: August 2014

SummaryCa2+ mobilization and cytoskeletal reorganization are key hallmarks of T‐cell activation, and their interdependence has long been recognized. Recent advances in the field have elucidated the molecular pathways that underlie these events and have revealed several points of intersection. Ca2+ signaling can be divided into two phases: initial events leading to release of Ca2+ from endoplasmic reticulum stores, and a second phase involving STIM 1 (stromal interaction molecule 1) clustering and CRAC (calcium release activated calcium) channel activation. Cytoskeletal dynamics promote both phases. During the first phase, the actin cytoskeleton promotes mechanotransduction and serves as a dynamic scaffold for microcluster assembly. Proteins that drive actin polymerization such as WASp (Wiskott–Aldrich syndrome protein) and HS1 (hematopoietic lineage cell‐specific protein 1) promote signaling through PLCγ1 (phospholipase Cγ1) and release of Ca2+ from endoplasmic reticulum stores. During the second phase, the WAVE (WASP‐family verprolin homologous protein) complex and the microtubule cytoskeleton promote STIM 1 clustering at sites of plasma membrane apposition, opening Orai channels. In addition, gross cell shape changes and organelle movements buffer local Ca2+ levels, leading to sustained Ca2+ mobilization. Conversely, elevated intracellular Ca2+ activates cytoskeletal remodeling. This can occur indirectly, via calpain activity, and directly, via Ca2+‐dependent cytoskeletal regulatory proteins such as myosin II and L‐plastin. While it is true that the cytoskeleton regulates Ca2+ responses and vice versa, interdependence between Ca2+ and the cytoskeleton also encompasses signaling events that occur in parallel, downstream of shared intermediates. Inositol cleavage by PLCγ1 simultaneously triggers both endoplasmic reticulum store release and diacylglycerol‐dependent microtubule organizing center reorientation, while depleting the pool of phosphatidylinositol‐4,5‐bisphosphate, an activator of multiple actin‐regulatory proteins. The close interdependence of Ca2+ signaling and cytoskeletal dynamics in T cells provides positive feedback mechanisms for T‐cell activation and allows for finely tuned responses to extracellular cues.
Neutrophil migration: moving from zebrafish models to human autoimmunity
Authors: Shelef Miriam A. , Tauzin Sebastien , Huttenlocher Anna 
Published: August 2014

SummaryThere has been a resurgence of interest in the neutrophil's role in autoimmune disease. Classically considered an early responder that dies at the site of inflammation, new findings using live imaging of embryonic zebrafish and other modalities suggest that neutrophils can reverse migrate away from sites of inflammation. These ‘inflammation‐sensitized’ neutrophils, as well as the neutrophil extracellular traps and other products made by neutrophils in general, may have many implications for autoimmunity. Here, we review what is known about the role of neutrophils in three different autoimmune diseases: rheumatoid arthritis, systemic lupus erythematosus, and small vessel vasculitis. We then highlight recent findings related to several cytoskeletal regulators that guide neutrophil recruitment including Lyn, Rac2, and SHIP. Finally, we discuss how our improved understanding of the molecules that control neutrophil chemotaxis may impact our knowledge of autoimmunity.