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1.
Immunol Rev ; 291(1): 104-122, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31402507

RESUMO

Although calcium signaling and the important role of calcium release-activated calcium channels is well recognized in the context of immune cell signaling, there is a vast diversity of ion channels and transporters that regulate the entry of ions beyond calcium, including magnesium, zinc, potassium, sodium, and chloride. These ions play a critical role in numerous metabolic and cellular processes. The importance of ions in human health and disease is illustrated by the identification of primary immunodeficiencies in patients with mutations in genes encoding ion channels and transporters, as well as the immunological defects observed in individuals with nutritional ion deficiencies. Despite progress in identifying the important role of ions in immune cell development and activation, we are still in the early stages of exploring the diversity of ion channels and transporters and mechanistically understanding the role of these ions in immune cell biology. Here, we review the biology of ion signaling in B cells and the identification of critical ion channels and transporters in B-cell development, activation, and differentiation into effector cells. Elucidating the role of ion channels and transporters in immune cell signaling is critical for expanding the repertoire of potential therapeutics for the treatment of immune disorders. Moreover, increased understanding of the role of ions in immune cell function will enhance our understanding of the potentially serious consequences of ion deficiencies in human health and disease.


Assuntos
Linfócitos B/imunologia , Linfócitos B/metabolismo , Sinalização do Cálcio , Cálcio/metabolismo , Canais Iônicos/metabolismo , Ativação Linfocitária/imunologia , Animais , Biomarcadores , Humanos , Sinapses Imunológicas/imunologia , Sinapses Imunológicas/metabolismo , Magnésio/metabolismo , Proteínas de Membrana Transportadoras/metabolismo , Transdução de Sinais
2.
Elife ; 82019 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-31157616

RESUMO

When B cells encounter antigens on the surface of an antigen-presenting cell (APC), B cell receptors (BCRs) are gathered into microclusters that recruit signaling enzymes. These microclusters then move centripetally and coalesce into the central supramolecular activation cluster of an immune synapse. The mechanisms controlling BCR organization during immune synapse formation, and how this impacts BCR signaling, are not fully understood. We show that this coalescence of BCR microclusters depends on the actin-related protein 2/3 (Arp2/3) complex, which nucleates branched actin networks. Moreover, in murine B cells, this dynamic spatial reorganization of BCR microclusters amplifies proximal BCR signaling reactions and enhances the ability of membrane-associated antigens to induce transcriptional responses and proliferation. Our finding that Arp2/3 complex activity is important for B cell responses to spatially restricted membrane-bound antigens, but not for soluble antigens, highlights a critical role for Arp2/3 complex-dependent actin remodeling in B cell responses to APC-bound antigens.


Assuntos
Proteína 3 Relacionada a Actina/metabolismo , Proteínas Semelhantes a Angiopoietina/metabolismo , Linfócitos B/imunologia , Sinapses Imunológicas/metabolismo , Ativação Linfocitária , Receptores de Antígenos de Linfócitos B/metabolismo , Transdução de Sinais , Actinas/metabolismo , Animais , Camundongos Endogâmicos C57BL
3.
Immunol Lett ; 209: 11-20, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30954509

RESUMO

Cell-cell communication comprises a variety of molecular mechanisms that immune cells use to respond appropriately to diverse pathogenic stimuli. T lymphocytes polarize in response to different stimuli, such as cytokines, adhesion to specific ligands and cognate antigens presented in the context of MHC. Polarization takes different shapes, from migratory front-back polarization to the formation of immune synapses (IS). The formation of IS between a T cell and an antigen-presenting cell involves early events of receptor-ligand interaction leading to the reorganization of the plasma membrane and the cytoskeleton to orchestrate vesicular and endosomal traffic and directed secretion of several types of mediators, including cytokines and nanovesicles. Cell polarization involves the repositioning of many subcellular organelles, including the endosomal compartment, which becomes an effective platform for the shuttling of molecules as vesicular cargoes that lately will be secreted to transfer information to antigen-presenting cells. Overall, the polarized interaction between a T cell and APC modifies the recipient cell in different ways that are likely lineage-dependent, e.g. dendritic cells, B cells or even other T cells. In this review, we will discuss the mechanisms that mediate the polarization of different membrane receptors, cytoskeletal components and organelles in T cells in a variety of immune contexts.


Assuntos
Comunicação Celular/imunologia , Ativação Linfocitária/imunologia , Linfócitos T/imunologia , Linfócitos T/metabolismo , Animais , Citocinas/metabolismo , Citoesqueleto/metabolismo , Endossomos/metabolismo , Humanos , Sinapses Imunológicas/imunologia , Sinapses Imunológicas/metabolismo , Mitocôndrias/metabolismo , Receptores de Antígenos de Linfócitos T , Vesículas Transportadoras/metabolismo
4.
J Immunol ; 202(6): 1715-1723, 2019 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-30718295

RESUMO

The immunological synapse (IS) is a superstructure formed during T cell activation at the zone of contact between T cells and dendritic cells (DCs). The IS includes specific molecular components in the T cell and DCs sides that may result in different functionality. Most of the studies on the IS have focused on the T cell side of this structure and, in contrast, the information available on the IS of DCs is sparse. Autophagy is a cellular process involved in the clearance of damaged proteins and organelles via lysosomal degradation. Mitophagy is the selective autophagy of damaged mitochondria. In this study, it is shown that IS formation induces clustering of mitochondria in the IS of DCs and partial depolarization of these organelles. At the IS of the DCs also accumulate autophagy and mitophagy markers, even when the kinase complex mTORC1, an inhibitor of the autophagy, is active. Together the results presented indicate that IS formation induces local clustering of mitochondria and mitophagy, which could be a homeostatic mechanism to control the quality of mitochondria in this region. The data underline the complexity of the regulatory mechanisms operating in the IS of DCs.


Assuntos
Células Dendríticas/metabolismo , Sinapses Imunológicas/metabolismo , Mitocôndrias/metabolismo , /imunologia , Animais , Células Dendríticas/imunologia , Sinapses Imunológicas/imunologia , Ativação Linfocitária/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Mitocôndrias/imunologia
5.
Front Immunol ; 10: 61, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30761133

RESUMO

The particular HLA class I variants an individual carries influences their resistance and susceptibility to a multitude of diseases. Expression level and variation in the peptide binding region correlates with, for example, a person's progression to AIDS after HIV infection. One factor which has not yet been addressed is whether or not different HLA class I proteins organize differently in the cell membrane on a nanoscale. Here, we examined the organization of three HLA-B allotypes (B*2705, B*5301, and B*5701) and two HLA-C allotypes (C*0602 and C*0702) in the membrane of 721.221 cells which otherwise lack expression of HLA-B or HLA-C. All these allotypes are ligands for the T cell receptor and leukocyte immunoglobulin-like receptors, but additionally, the HLA-B allotypes are ligands for the killer-cell immunoglobulin-like receptor family member KIR3DL1, HLA-C*0602 is a ligand for KIR2DL1, and HLA-C*0702 is a ligand for KIR2DL2/3. Using super-resolution microscopy, we found that both HLA-B and HLA-C formed more clusters and a greater proportion of HLA contributed to clusters, when expressed at lower levels. Thus, HLA class I organization is a covariate in genetic association studies of HLA class I expression level with disease progression. Surprisingly, we also found that HLA-C was more clustered than HLA-B when expression level was controlled. HLA-C consistently formed larger and more numerous clusters than HLA-B and a greater proportion of HLA-C contributed to clusters than for HLA-B. We also found that the organization of HLA class I proteins varied with cell type. T cells exhibited a particularly clustered organization of HLA class I while B cells expressed a more uniform distribution. In summary, HLA class I variants are organized differently in the cell surface membrane which may impact their functions.


Assuntos
Membrana Celular/metabolismo , Antígenos HLA-B/imunologia , Antígenos HLA-C/metabolismo , Sequência de Aminoácidos , Linfócitos B/imunologia , Linfócitos B/metabolismo , Cisteína/química , Imunofluorescência , Expressão Gênica , Antígenos HLA-B/química , Antígenos HLA-B/genética , Antígenos HLA-B/metabolismo , Antígenos HLA-C/química , Antígenos HLA-C/genética , Antígenos HLA-C/imunologia , Humanos , Sinapses Imunológicas/imunologia , Sinapses Imunológicas/metabolismo , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/metabolismo , Ligação Proteica
6.
Front Immunol ; 9: 2898, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30581442

RESUMO

The conformational dynamism of proteins is well established. Rather than having a single structure, proteins are more accurately described as a conformational ensemble that exists across a rugged energy landscape, where different conformational sub-states interconvert. The interaction between αß T cell receptors (TCR) and cognate peptide-MHC (pMHC) is no exception, and is a dynamic process that involves substantial conformational change. This review focuses on technological advances that have begun to establish the role of conformational dynamics and dynamic allostery in TCR recognition of the pMHC and the early stages of signaling. We discuss how the marriage of molecular dynamics (MD) simulations with experimental techniques provides us with new ways to dissect and interpret the process of TCR ligation. Notably, application of simulation techniques lags behind other fields, but is predicted to make substantial contributions. Finally, we highlight integrated approaches that are being used to shed light on some of the key outstanding questions in the early events leading to TCR signaling.


Assuntos
Antígenos de Histocompatibilidade Classe I/metabolismo , Ativação Linfocitária , Receptores de Antígenos de Linfócitos T alfa-beta/metabolismo , Linfócitos T/imunologia , Cristalografia por Raios X , Antígenos de Histocompatibilidade Classe I/imunologia , Humanos , Sinapses Imunológicas/imunologia , Sinapses Imunológicas/metabolismo , Simulação de Dinâmica Molecular , Ressonância Magnética Nuclear Biomolecular , Estrutura Terciária de Proteína , Receptores de Antígenos de Linfócitos T alfa-beta/imunologia , Espalhamento a Baixo Ângulo , Espectrometria de Fluorescência , Linfócitos T/metabolismo
7.
Cell Rep ; 25(11): 3110-3122.e6, 2018 12 11.
Artigo em Inglês | MEDLINE | ID: mdl-30540943

RESUMO

Complete activation of B cells relies on their capacity to extract tethered antigens from immune synapses by either exerting mechanical forces or promoting their proteolytic degradation through lysosome secretion. Whether antigen extraction can also be tuned by local cues originating from the lymphoid microenvironment has not been investigated. We here show that the expression of Galectin-8-a glycan-binding protein found in the extracellular milieu, which regulates interactions between cells and matrix proteins-is increased within lymph nodes under inflammatory conditions where it enhances B cell arrest phases upon antigen recognition in vivo and promotes synapse formation during BCR recognition of immobilized antigens. Galectin-8 triggers a faster recruitment and secretion of lysosomes toward the B cell-antigen contact site, resulting in efficient extraction of immobilized antigens through a proteolytic mechanism. Thus, extracellular cues can determine how B cells sense and extract tethered antigens and thereby tune B cell responses in vivo.


Assuntos
Apresentação do Antígeno/imunologia , Antígenos de Superfície/metabolismo , Linfócitos B/imunologia , Galectinas/metabolismo , Sinapses Imunológicas/metabolismo , Animais , Linfócitos B/citologia , Pontos de Checagem do Ciclo Celular , Linhagem Celular , Galinhas , Linfonodos/metabolismo , Lisossomos/metabolismo , Camundongos Endogâmicos C57BL , Ligação Proteica , Proteólise , Ratos , Receptores de Antígenos de Linfócitos B/metabolismo , Linfócitos T/citologia
8.
Front Immunol ; 9: 2486, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30416506

RESUMO

A major obstacle for chimeric antigen receptor (CAR) T cell therapy in solid tumors is the lack of truly tumor-specific target antigens, which translates to the targeting of tumor-associated antigens (TAAs) overexpressed on tumors but shared with normal organs, raising safety concerns. In addition, expression of TAAs in solid tumors is particularly heterogeneous. In this regard, it is critical to deeply understand the sensitivity of CAR T cells, especially against low-density targets and the possible therapeutic window of antigen density targeted by CAR T cells. In this review, we discuss the recent findings of mechanisms of antigen recognition through CAR, including immunological synapse formation, and the impact of target antigen density for induction of distinct T cell functions. We also discuss rational strategies to adjust and expand the therapeutic window for effective and safe targeting of solid tumors by CAR T cell platforms.


Assuntos
Sinapses Imunológicas/metabolismo , Imunoterapia Adotiva/métodos , Neoplasias/terapia , Receptores de Antígenos de Linfócitos T/genética , Linfócitos T/imunologia , Animais , Antígenos de Neoplasias/imunologia , Humanos , Neoplasias/imunologia , Linfócitos T/transplante
9.
Adv Immunol ; 140: 21-57, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30366518

RESUMO

The tumor necrosis factor receptor superfamily (TNFRSF) and their ligands mediate lymphoid tissue development and homeostasis in addition to key aspects of innate and adaptive immune responses. T cells of the adaptive immune system express a number of TNFRSF members that are used to receive signals at different instructive stages and produce several tumor necrosis factor superfamily (TNFSF) members as effector molecules. There is also one example of a TNFRSF member serving as a ligand for negative regulatory checkpoint receptors. In most cases, the ligands in afferent and efferent phases are membrane proteins and thus the interaction with TNFRSF members must take place in immunological synapses and other modes of cell-cell interaction. A particular feature of the TNFRSF-mediated signaling is the prominent use of linear ubiquitin chains as scaffolds for signaling complexes that activate nuclear factor κ-B and Fos/Jun transcriptional regulators. This review will focus on the signaling mechanisms triggered by TNFRSF members in their role as costimulators of early and late phases of T cell instruction and the delivery mechanism of TNFSF members through the immunological synapses of helper and cytotoxic effector cells.


Assuntos
Sinapses Imunológicas/metabolismo , Receptores do Fator de Necrose Tumoral/metabolismo , Linfócitos T Citotóxicos/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Animais , Homeostase , Humanos , Ativação Linfocitária , NF-kappa B/metabolismo , Receptores de Antígenos de Linfócitos T/metabolismo , Transdução de Sinais , Ativação Transcricional
10.
Front Immunol ; 9: 2027, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30237801

RESUMO

Bruton's tyrosine kinase (Btk) has a key role in the signaling pathways of receptors essential for the B lymphocyte response. Given its implication in B cell-related immunodeficiencies, leukemias/lymphomas and autoimmunity, Btk is studied intensely and is a target for therapy. Here, using primary B cells from distinct mouse models and the pharmacological inhibitors ibrutinib and acalabrutinib, we report distinct roles for Btk in antigen-triggered immune synapse (IS) formation. Btk recruitment to the plasma membrane regulates the B cell ability to trigger IS formation as well as its appropriate molecular assembly; Btk shuttling/scaffold activities seem more relevant than the kinase function on that. Btk-kinase activity controls antigen accumulation at the IS through the PLCγ2/Ca2+ axis. Impaired Btk membrane-recruitment or kinase function likewise alters antigen-triggered microtubule-organizing center (MTOC) polarization to the IS, B cell activation and proliferation. Data also show that, for B cell function, IS architecture is as important as the quantity of antigen that accumulates at the synapse.


Assuntos
Tirosina Quinase da Agamaglobulinemia/metabolismo , Linfócitos B/imunologia , Membrana Celular/metabolismo , Sinapses Imunológicas/metabolismo , Tirosina Quinase da Agamaglobulinemia/antagonistas & inibidores , Tirosina Quinase da Agamaglobulinemia/genética , Animais , Antígenos/metabolismo , Benzamidas/farmacologia , Sinalização do Cálcio , Polaridade Celular , Proliferação de Células , Células Cultivadas , Ativação Linfocitária , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos CBA , Camundongos Knockout , Centro Organizador dos Microtúbulos , Mutação/genética , Fosfolipase C gama/metabolismo , Transporte Proteico , Pirazinas/farmacologia , Pirazóis/farmacologia , Pirimidinas/farmacologia , Receptores de Antígenos de Linfócitos B/metabolismo
11.
Immunity ; 49(3): 427-437.e4, 2018 09 18.
Artigo em Inglês | MEDLINE | ID: mdl-30217409

RESUMO

How cytotoxic T lymphocytes (CTLs) sense T cell receptor (TCR) signaling in order to specialize an area of plasma membrane for granule secretion is not understood. Here, we demonstrate that immune synapse formation led to rapid localized changes in the phosphoinositide composition of the plasma membrane, both reducing phosphoinositide-4-phosphate (PI(4)P), PI(4,5)P2, and PI(3,4,5)P3 and increasing diacylglycerol (DAG) and PI(3,4)P2 within the first 2 min of synapse formation. These changes reduced negative charge across the synapse, triggering the release of electrostatically bound PIP5 kinases that are required to replenish PI(4,5)P2. As PI(4,5)P2 decreased, actin was depleted from the membrane, allowing secretion. Forced localization of PIP5Kß across the synapse prevented actin depletion, blocking both centrosome docking and secretion. Thus, PIP5Ks act as molecular sensors of TCR activation, controlling actin recruitment across the synapse, ensuring exquisite co-ordination between TCR signaling and CTL secretion.


Assuntos
Actinas/metabolismo , Membrana Celular/metabolismo , Grânulos Citoplasmáticos/metabolismo , Sinapses Imunológicas/metabolismo , Fosfatidilinositóis/metabolismo , Fosfotransferases (Aceptor do Grupo Álcool)/metabolismo , Linfócitos T Citotóxicos/imunologia , Animais , Degranulação Celular , Linhagem Celular , Citotoxicidade Imunológica , Ativação Linfocitária , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Receptores de Antígenos de Linfócitos T/metabolismo , Transdução de Sinais
12.
Cell Rep ; 24(5): 1151-1162, 2018 07 31.
Artigo em Inglês | MEDLINE | ID: mdl-30067972

RESUMO

During immunological synapse (IS) formation, T cell receptor (TCR) signaling complexes, integrins, and costimulatory molecules exhibit a particular spatial localization. Here, we develop an agent-based model for the IS formation based on TCR peptide-bound major histocompatibility complex (pMHC) and leukocyte-function-associated antigen 1 (LFA-1) intracellular activation molecule 1 (ICAM-1) dynamics, including CD28 binding to a costimulatory ligand, coupling of molecules to the centripetal actin flow, and size-based segregation (SBS). A radial gradient of LFA-1 in the peripheral supramolecular activation cluster (pSMAC) toward the central supramolecular activation cluster (cSMAC) emerged as a combined consequence of actin binding and diffusion and modified the positioning of other molecules. The simulations predict a mechanism of CD28 movement, according to which CD28-CD80 complexes passively follow TCR-pMHC microclusters. However, the characteristic CD28-CD80 localization in a ring pattern around the cSMAC only emerges with a particular CD28-actin coupling strength that induces a centripetal motion. These results have implications for the understanding of T cell activation and fate decisions.


Assuntos
Actinas/metabolismo , Antígeno B7-1/metabolismo , Antígenos CD28/metabolismo , Simulação por Computador , Sinapses Imunológicas/metabolismo , Animais , Humanos , Transporte Proteico , Transdução de Sinais
13.
Immunol Rev ; 285(1): 194-205, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-30129204

RESUMO

T cells initiate and regulate adaptive immune responses that can clear infections. To do this, they use their T cell receptors (TCRs) to continually scan the surfaces of other cells for cognate peptide antigens presented on major histocompatibility complexes (pMHCs). Experimental work has established that as few 1-10 pMHCs are sufficient to activate T cells. This sensitivity is remarkable in light of a number of factors, including the observation that the TCR and pMHC are short molecules relative to highly abundant long surface molecules, such as CD45, that can hinder initial binding, and moreover, the TCR/pMHC interaction is of weak affinity with solution lifetimes of approximately 1 second. Here, we review experimental and mathematical work that has contributed to uncovering molecular mechanisms of T cell sensitivity. We organize the mechanisms by where they act in the pathway to activate T cells, namely mechanisms that (a) promote TCR/pMHC binding, (b) induce rapid TCR signaling, and (c) amplify TCR signaling. We discuss work showing that high sensitivity reduces antigen specificity unless molecular feedbacks are invoked. We conclude by summarizing a number of open questions.


Assuntos
Sinapses Imunológicas/metabolismo , Modelos Imunológicos , Linfócitos T/imunologia , Animais , Apresentação do Antígeno , Antígenos de Histocompatibilidade/metabolismo , Humanos , Ativação Linfocitária , Modelos Teóricos , Ligação Proteica , Receptores de Antígenos de Linfócitos T/metabolismo , Transdução de Sinais
14.
Nat Commun ; 9(1): 2618, 2018 07 05.
Artigo em Inglês | MEDLINE | ID: mdl-29976994

RESUMO

The T-cell antigen receptor (TCR) is pre-organised in oligomers, known as nanoclusters. Nanoclusters could provide a framework for inter-TCR cooperativity upon peptide antigen-major histocompatibility complex (pMHC) binding. Here we have used soluble pMHC oligomers in search for cooperativity effects along the plasma membrane plane. We find that initial binding events favour subsequent pMHC binding to additional TCRs, during a narrow temporal window. This behaviour can be explained by a 3-state model of TCR transition from Resting to Active, to a final Inhibited state. By disrupting nanoclusters and hampering the Active conformation, we show that TCR cooperativity is consistent with TCR nanoclusters adopting the Active state in a coordinated manner. Preferential binding of pMHC to the Active TCR at the immunological synapse suggests that there is a transient time frame for signal amplification in the TCR, allowing the T cells to keep track of antigen quantity and binding time.


Assuntos
Antígenos de Histocompatibilidade/imunologia , Peptídeos/imunologia , Receptores de Antígenos de Linfócitos T/imunologia , Linfócitos T/imunologia , Animais , Sítios de Ligação , Antígenos de Histocompatibilidade/química , Antígenos de Histocompatibilidade/metabolismo , Humanos , Sinapses Imunológicas/imunologia , Sinapses Imunológicas/metabolismo , Camundongos Transgênicos , Modelos Moleculares , Peptídeos/química , Peptídeos/metabolismo , Ligação Proteica , Conformação Proteica , Multimerização Proteica , Receptores de Antígenos de Linfócitos T/química , Receptores de Antígenos de Linfócitos T/metabolismo , Transdução de Sinais/imunologia , Linfócitos T/metabolismo
15.
Nat Immunol ; 19(8): 838-848, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29988091

RESUMO

Foxo transcription factors play an essential role in regulating specialized lymphocyte functions and in maintaining T cell quiescence. Here, we used a system in which Foxo1 transcription-factor activity, which is normally terminated upon cell activation, cannot be silenced, and we show that enforcing Foxo1 activity disrupts homeostasis of CD4 conventional and regulatory T cells. Despite limiting cell metabolism, continued Foxo1 activity is associated with increased activation of the kinase Akt and a cell-intrinsic proliferative advantage; however, survival and cell division are decreased in a competitive setting or growth-factor-limiting conditions. Via control of expression of the transcription factor Myc and the IL-2 receptor ß-chain, termination of Foxo1 signaling couples the increase in cellular cholesterol to biomass accumulation after activation, thereby facilitating immunological synapse formation and mTORC1 activity. These data reveal that Foxo1 regulates the integration of metabolic and mitogenic signals essential for T cell competitive fitness and the coordination of cell growth with cell division.


Assuntos
Linfócitos T CD4-Positivos/fisiologia , Proteína Forkhead Box O1/metabolismo , Linfócitos T Reguladores/fisiologia , Animais , Proliferação de Células , Células Cultivadas , Colesterol/metabolismo , Proteína Forkhead Box O1/genética , Perfilação da Expressão Gênica , Homeostase , Sinapses Imunológicas/metabolismo , Subunidade beta de Receptor de Interleucina-2/genética , Subunidade beta de Receptor de Interleucina-2/metabolismo , Ativação Linfocitária , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Camundongos , Camundongos Knockout , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo , Transdução de Sinais
16.
Mol Immunol ; 101: 319-328, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-30036798

RESUMO

B cell encounter with antigen displayed on antigen-presenting cells leads to B cell immune synapse formation, internalisation of the antigen, and stimulation of antibody responses. The sensitivity with which B cells detect antigen, and the quality and quantity of antigen that B cells acquire, depend upon mechanical properties of the immune synapse including interfacial tension, the strength of intermolecular bonds, and the compliance of the molecules and membranes that participate in antigen presentation. In this review, we discuss our current understanding of how these various physical parameters influence B cell antigen extraction in the immune synapse and how a more comprehensive understanding of B cell mechanics may promote the development of new approaches to stimulate the production of desired antibodies.


Assuntos
Antígenos/metabolismo , Linfócitos B/metabolismo , Sinapses Imunológicas/metabolismo , Animais , Apresentação do Antígeno/imunologia , Células Apresentadoras de Antígenos/imunologia , Fenômenos Biofísicos , Humanos
17.
Sci Rep ; 8(1): 10668, 2018 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-30006566

RESUMO

Despite advances in the clinical management of hepatocellular carcinoma (HCC), this form of cancer remains the second leading cause of cancer-related death worldwide. Currently, there are few treatment options for advanced HCC. Therefore, novel treatment strategies for HCC are required. Here, we described the promising antitumour effects of anisomycin, which exerts both direct killing effects and natural killer cell (NK)-mediated immunotherapeutic effects in HCC. To better elucidate the mechanisms through which anisomycin mediates its antitumour effects, we performed a genome-scale transcriptional analysis. We found that anisomycin treatment of HCC differentially modulated a broad range of immune regulation-associated genes. Among these immune regulation-associated genes, we found that lymphocyte function-associated antigen-3 (LFA-3, also called CD58), whose expression was significantly increased in anisomycin-treated HCC cells, was a critical player in NK-mediated immunotherapeutic effects. Furthermore major histocompatibility complex molecules class I (MHC-I) on HCC cells were also significantly regulated by treatment of anisomycin. Those adhesion molecules like CD58, MHC-I, and ICAM4 should be important for immune synapse formation between NK cells and HCC cells to boost NK-mediated immunotherapeutic effects. Notably, this is the first report of NK-dependent immunomodulatory effects of anisomycin suggesting anisomycin as a novel therapeutic drug for treatment of HCC.


Assuntos
Anisomicina/farmacologia , Carcinoma Hepatocelular/terapia , Imunoterapia/métodos , Células Matadoras Naturais/efeitos dos fármacos , Neoplasias Hepáticas/terapia , Animais , Anisomicina/uso terapêutico , Antígenos CD58/imunologia , Antígenos CD58/metabolismo , Carcinoma Hepatocelular/imunologia , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/imunologia , Antígenos de Histocompatibilidade Classe I/imunologia , Antígenos de Histocompatibilidade Classe I/metabolismo , Humanos , Sinapses Imunológicas/efeitos dos fármacos , Sinapses Imunológicas/imunologia , Sinapses Imunológicas/metabolismo , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/metabolismo , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/patologia , Camundongos , Análise de Sequência com Séries de Oligonucleotídeos , Resultado do Tratamento , Ensaios Antitumorais Modelo de Xenoenxerto
18.
Front Immunol ; 9: 1174, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29910809

RESUMO

The different cytoskeleton systems and their connecting molecular motors move vesicles and intracellular organelles to shape cells. Polarized cells with specialized functions display an exquisite spatio-temporal regulation of both cytoskeletal and organelle arrangements that support their specific tasks. In particular, T cells rapidly change their shape and cellular function through the establishment of cell surface and intracellular polarity in response to a variety of cues. This review focuses on the contribution of the microtubule-based dynein/dynactin motor complex, the tubulin and actin cytoskeletons, and different organelles to the formation of the antigen-driven immune synapse.


Assuntos
Citoesqueleto de Actina/metabolismo , Sinapses Imunológicas/metabolismo , Microtúbulos/metabolismo , Tubulina (Proteína)/metabolismo , Animais , Antígenos/metabolismo , Polaridade Celular , Complexo Dinactina/metabolismo , Dineínas/metabolismo , Humanos , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Tubulina (Proteína)/química
19.
Mol Immunol ; 101: 140-145, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29935436

RESUMO

The capacity of B lymphocytes to produce specific antibodies, particularly broadly neutralizing antibodies that provide immunity to viral pathogens has positioned them as valuable therapeutic targets for immunomodulation. To become competent as antibody secreting cells, B cells undergo a series of activation steps, which are triggered by the recognition of antigens frequently displayed on the surface of other presenting cells. Such antigens elicit the formation of an immune synapse (IS), where local cytoskeleton rearrangements coupled to mechanical forces and membrane trafficking orchestrate the extraction and processing of antigens in B cells. In this review, we discuss the molecular mechanisms that regulate polarized membrane trafficking and mechanical properties of the immune synapse, as well as the potential extracellular cues from the environment, which may impact the ability of B cells to sense and acquire antigens at the immune synapse. An integrated view of the diverse cellular mechanisms that shape the immune synapse will provide a better understanding on how B cells are efficiently activated.


Assuntos
Antígenos/metabolismo , Linfócitos B/metabolismo , Membrana Celular/metabolismo , Polaridade Celular , Animais , Humanos , Sinapses Imunológicas/metabolismo , Transporte Proteico
20.
Cell Rep ; 23(6): 1794-1805, 2018 05 08.
Artigo em Inglês | MEDLINE | ID: mdl-29742434

RESUMO

During sexual intercourse, HIV-1 crosses epithelial barriers composing the genital mucosa, a poorly understood feature that requires an HIV-1-infected cell vectoring efficient mucosal HIV-1 entry. Therefore, urethral mucosa comprising a polarized epithelium and a stroma composed of fibroblasts and macrophages were reconstructed in vitro. Using this system, we demonstrate by live imaging that efficient HIV-1 transmission to stromal macrophages depends on cell-mediated transfer of the virus through virological synapses formed between HIV-1-infected CD4+ T cells and the epithelial cell mucosal surface. We visualized HIV-1 translocation through mucosal epithelial cells via transcytosis in regions where virological synapses occurred. In turn, interleukin-13 is secreted and HIV-1 targets macrophages, which develop a latent state of infection reversed by lipopolysaccharide (LPS) activation. The live observation of virological synapse formation reported herein is key in the design of vaccines and antiretroviral therapies aimed at blocking HIV-1 access to cellular reservoirs in genital mucosa.


Assuntos
Linfócitos T CD4-Positivos/imunologia , HIV-1/fisiologia , Imagem Tridimensional , Sinapses Imunológicas/virologia , Macrófagos/virologia , Adulto , Epitélio/virologia , Infecções por HIV/imunologia , Infecções por HIV/virologia , Humanos , Sinapses Imunológicas/metabolismo , Macrófagos/patologia , Macrófagos/ultraestrutura , Masculino , Modelos Biológicos , Membrana Mucosa/virologia , Células Estromais/patologia , Células Estromais/ultraestrutura , Células Estromais/virologia , Uretra/patologia , Vírion/metabolismo , Vírion/ultraestrutura
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