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1.
Nat Commun ; 12(1): 1344, 2021 02 26.
Artigo em Inglês | MEDLINE | ID: mdl-33637722

RESUMO

During cellular differentiation chromosome conformation is intricately remodelled to support the lineage-specific transcriptional programs required for initiating and maintaining lineage identity. When these changes occur in relation to cell cycle, division and time in response to cellular activation and differentiation signals has yet to be explored, although it has been proposed to occur during DNA synthesis or after mitosis. Here, we elucidate the chromosome conformational changes in B lymphocytes as they differentiate and expand from a naive, quiescent state into antibody secreting plasma cells. We find gene-regulatory chromosome reorganization in late G1 phase before the first division, and that this configuration is remarkably stable as the cells massively and rapidly clonally expand. A second wave of conformational change occurs as cells terminally differentiate into plasma cells, coincident with increased time in G1 phase. These results provide further explanation for how lymphocyte fate is imprinted prior to the first division. They also suggest that chromosome reconfiguration occurs prior to DNA replication and mitosis, and is linked to a gene expression program that controls the differentiation process required for the generation of immunity.


Assuntos
Linfócitos B/fisiologia , Diferenciação Celular/genética , Diferenciação Celular/fisiologia , Genoma , Ativação Linfocitária/genética , Ativação Linfocitária/fisiologia , Animais , Células Produtoras de Anticorpos , Ciclo Celular , Divisão Celular , Cromatina , Cromossomos , Replicação do DNA , Epigenômica , Fase G1/genética , Regulação da Expressão Gênica , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Mitose , Plasmócitos
2.
Mol Immunol ; 130: 1-6, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33340930

RESUMO

The capacity of α-galactosylceramide (α-GalCer) to act as an anti-cancer agent in mice through the specific stimulation of type I NKT (iNKT) cells has prompted extensive investigation to translate this finding to the clinic. However, low frequencies of iNKT cells in cancer patients and their hypo-responsiveness to repeated stimulation have been seen as barriers to its efficacy. Currently the most promising clinical application of α-GalCer, or its derivatives, is as stimuli for ex vivo expansion of iNKT cells for adoptive therapy, although some encouraging clinical results have recently been reported using α-GalCer pulsed onto large numbers of antigen presenting cells (APCs). In on-going preclinical studies, attempts to improve efficacy of injected iNKT cell agonists have focussed on optimising presentation in vivo, through encapsulation in particulate vectors, making structural changes that help binding to the presenting molecule CD1d, or injecting agonists covalently attached to recombinant CD1d. Variations on these same approaches are being used to enhance the APC-licencing function of iNKT cells in vivo to induce adaptive immune responses to associated tumour antigens. Looking ahead, a unique capacity of in vivo-activated iNKT cells to facilitate formation of resident memory CD8+ T cells is a new observation that could find a role in cancer therapy.


Assuntos
Galactosilceramidas/uso terapêutico , Imunoterapia/métodos , Ativação Linfocitária/efeitos dos fármacos , Células T Matadoras Naturais/efeitos dos fármacos , Neoplasias/terapia , Adjuvantes Imunológicos/uso terapêutico , Animais , Células Apresentadoras de Antígenos/imunologia , Linfócitos T CD8-Positivos/imunologia , Vacinas Anticâncer/uso terapêutico , Galactosilceramidas/farmacologia , Humanos , Ativação Linfocitária/fisiologia , Células T Matadoras Naturais/fisiologia , Células T Matadoras Naturais/transplante , Neoplasias/imunologia
3.
Mol Immunol ; 130: 55-63, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33360377

RESUMO

The field of mucosal-associated invariant T cell (MAIT) biology has grown rapidly since the identification of the vitamin-B-based antigens recognised by these specialised T cells. Over the past few years, our understanding of the complexities of MAIT cell function has developed, as they find their place among the other better known cells of the immune system. Key questions relate to understanding when MAIT cells help, when they hinder or cause harm, and when they do not matter. Exploiting mouse strains that differ in MAIT cell numbers, leveraged by specific detection of MAIT cells using MR1-tetramers, it has now been shown that MAIT cells play important immune roles in settings that include bacterial and viral infections, autoimmune diseases and cancer. We have also learnt much about their development, modes of activation and response to commensal microbiota, and begun to try ways to manipulate MAIT cells to improve disease outcomes. Here we review recent studies that have assessed MAIT cells in models of disease.


Assuntos
Camundongos , Modelos Animais , Células T Invariáveis Associadas à Mucosa/fisiologia , Animais , Doenças Autoimunes/imunologia , Doenças Autoimunes/patologia , Humanos , Infecções/imunologia , Ativação Linfocitária/fisiologia , Neoplasias/imunologia , Neoplasias/patologia
5.
J Vis Exp ; (161)2020 07 23.
Artigo em Inglês | MEDLINE | ID: mdl-32773764

RESUMO

Traction force microscopy (TFM) enables the measurement of forces produced by a cell on a substrate. This technique infers traction force measurements from an experimentally observed displacement field produced by a cell pulling on an elastic substrate. Here, we adapted TFM to investigate the spatial and temporal structure of the force field exerted by B cells when activated by antigen engagement of the B cell receptor. Gel rigidity, bead density, and protein functionalization must be optimized for the study of relatively small cells (~ 6 µm) that interact with, and respond specifically to ligands for cell surface receptors.


Assuntos
Ativação Linfocitária/fisiologia , Microscopia de Força Atômica/métodos , Humanos
6.
Nat Commun ; 11(1): 3989, 2020 08 10.
Artigo em Inglês | MEDLINE | ID: mdl-32778653

RESUMO

Upon stimulation, B cells assume heterogeneous cell fates, with only a fraction differentiating into antibody-secreting cells (ASC). Here we investigate B cell fate programming and heterogeneity during ASC differentiation using T cell-independent models. We find that maximal ASC induction requires at least eight cell divisions in vivo, with BLIMP-1 being required for differentiation at division eight. Single cell RNA-sequencing of activated B cells and construction of differentiation trajectories reveal an early cell fate bifurcation. The ASC-destined branch requires induction of IRF4, MYC-target genes, and oxidative phosphorylation, with the loss of CD62L expression serving as a potential early marker of ASC fate commitment. Meanwhile, the non-ASC branch expresses an inflammatory signature, and maintains B cell fate programming. Finally, ASC can be further subseted based on their differential responses to ER-stress, indicating multiple development branch points. Our data thus define the cell division kinetics of B cell differentiation in vivo, and identify the molecular trajectories of B cell fate and ASC formation.


Assuntos
Células Produtoras de Anticorpos/metabolismo , Linfócitos B/imunologia , Ativação Linfocitária/fisiologia , Animais , Antígenos CD19/genética , Diferenciação Celular/genética , Diferenciação Celular/fisiologia , Imunidade , Fatores Reguladores de Interferon/metabolismo , Selectina L , Ativação Linfocitária/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fator 1 de Ligação ao Domínio I Regulador Positivo/genética , Fator 1 de Ligação ao Domínio I Regulador Positivo/metabolismo , Transcriptoma
7.
Proc Natl Acad Sci U S A ; 117(37): 22910-22919, 2020 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-32859758

RESUMO

Lymphocyte-based immunotherapy has emerged as a breakthrough in cancer therapy for both hematologic and solid malignancies. In a subpopulation of cancer patients, this powerful therapeutic modality converts malignancy to clinically manageable disease. However, the T cell- and chimeric antigen receptor T (CAR-T) cell-mediated antimetastatic activity, especially their impacts on microscopic metastatic lesions, has not yet been investigated. Here we report a living zebrafish model that allows us to visualize the metastatic cancer cell killing effect by tumor- infiltrating lymphocytes (TILs) and CAR-T cells in vivo at the single-cell level. In a freshly isolated primary human melanoma, specific TILs effectively eliminated metastatic cancer cells in the living body. This potent metastasis-eradicating effect was validated using a human lymphoma model with CAR-T cells. Furthermore, cancer-associated fibroblasts protected metastatic cancer cells from T cell-mediated killing. Our data provide an in vivo platform to validate antimetastatic effects by human T cell-mediated immunotherapy. This unique technology may serve as a precision medicine platform for assessing anticancer effects of cellular immunotherapy in vivo before administration to human cancer patients.


Assuntos
Imunoterapia/métodos , Linfócitos do Interstício Tumoral/metabolismo , Análise de Célula Única/métodos , Animais , Linhagem Celular Tumoral , Citotoxicidade Imunológica/imunologia , Imunoterapia Adotiva/métodos , Ativação Linfocitária/fisiologia , Modelos Animais , Metástase Neoplásica/patologia , Neoplasias/metabolismo , Receptores de Antígenos de Linfócitos T/imunologia , Linfócitos T/imunologia , Ensaios Antitumorais Modelo de Xenoenxerto/métodos , Peixe-Zebra
8.
Nat Immunol ; 21(8): 927-937, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32632289

RESUMO

In response to pathogenic threats, naive T cells rapidly transition from a quiescent to an activated state, yet the underlying mechanisms are incompletely understood. Using a pulsed SILAC approach, we investigated the dynamics of mRNA translation kinetics and protein turnover in human naive and activated T cells. Our datasets uncovered that transcription factors maintaining T cell quiescence had constitutively high turnover, which facilitated their depletion following activation. Furthermore, naive T cells maintained a surprisingly large number of idling ribosomes as well as 242 repressed mRNA species and a reservoir of glycolytic enzymes. These components were rapidly engaged following stimulation, promoting an immediate translational and glycolytic switch to ramp up the T cell activation program. Our data elucidate new insights into how T cells maintain a prepared state to mount a rapid immune response, and provide a resource of protein turnover, absolute translation kinetics and protein synthesis rates in T cells ( https://www.immunomics.ch ).


Assuntos
Ativação Linfocitária/fisiologia , Biossíntese de Proteínas/imunologia , Linfócitos T/imunologia , Humanos , RNA Mensageiro/imunologia , RNA Mensageiro/metabolismo , Fatores de Transcrição/imunologia , Fatores de Transcrição/metabolismo
9.
Expert Opin Biol Ther ; 20(9): 1025-1031, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32700604

RESUMO

INTRODUCTION: The globally rampant SARS CoV-2 pandemic requires novel medical strategies to control the severity of disease and death due to complications. Of the 15-20% patients that develop pulmonary symptoms, a sub-set develops an acute respiratory distress syndrome (ARDS) rapidly progressing into a critical condition. Marked elevation of cytokines/chemokines is observed with elevation of additional markers of inflammation, coagulation, and organ damage such as CRP, D-dimer, LDH, Ferritin and Troponin-I. This hyperinflammation leads to worsening of oxygen saturation due to pulmonary infiltration and exudation, organ damage, and dysfunction of coagulation pathway and may lead to multi-organ failure. AREAS COVERED: The role of anti-inflammatory monoclonal antibodies such as Itolizumab, in cytokine storm. EXPERT OPINION: Itolizumab, an anti-CD6 humanized IgG1 mAb, binds to domain-1 of CD-6 that is responsible for priming, activation, and differentiation of T-cells. Itolizumab significantly reduces T-cell proliferation along with substantial downregulation of the production of cytokines/chemokines. Approved for moderate to severe chronic plaque psoriasis in 2013 it is currently being studied for addressing COVID-19 related cytokine storm and its complications. This article reviews its use in COVID-19 infections; its dose, administration protocol, contra-indications, and safety in treating moderate-to-severe ARDS by preventing and treating the cytokine storm and its complications.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Antígenos CD/imunologia , Antígenos de Diferenciação de Linfócitos T/imunologia , Betacoronavirus , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/imunologia , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/imunologia , Anticorpos Monoclonais Humanizados/farmacologia , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/fisiologia , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/fisiologia , Citocinas/antagonistas & inibidores , Citocinas/imunologia , Humanos , Ativação Linfocitária/efeitos dos fármacos , Ativação Linfocitária/fisiologia , Pandemias , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Resultado do Tratamento
10.
J Cancer Res Clin Oncol ; 146(9): 2319-2327, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32592066

RESUMO

PURPOSE: Lymphocyte activation gene-3 (LAG3) is an immunosuppressive checkpoint molecule expressed on T cells. The frequency and distribution of LAG3 expression in oesophageal adenocarcinoma (EAC) is unknown. Aim of the study was the evaluation and distribution of LAG3 on tumour infiltrating lymphocytes (TILs) and correlation with clinico-pathological and molecular data. METHODS: We analysed tumor tissue samples using immunohistochemistry, multi-colour immunofluorescence and mRNA in-situ technology. The analyses were performed on a multi-spot tissue microarray (TMA) with 165 samples, followed by an evaluation on a single-spot TMA with 477 samples. These results were correlated with clinical and molecular tumour data. RESULTS: LAG3 expression on TILs was detectable in 10.5% on the multi-spot TMA and 11.4% on the single-spot TMA. There was a strong correlation between protein expression and mRNA expression (p < 0.001) in TILs. LAG 3 expression was correlated with CD4+ and CD8+ T-cells within the tumor (p < 0.001). LAG3 expression showed an improved overall survival (OS) compared to patients without LAG3 expression (median OS 70.2 vs. 26.9 months; p = 0.046). The effect was even clearer in the group of patients with tumour stages > pT2 (70.2 vs 25.0 months; p = 0.037). CONCLUSION: This is the first description of LAG3 expression on TILs in EAC, underscoring the importance of immunomodulation in EAC. Our data suggest an impact of LAG3 in a relevant subset of EAC. Therapeutic studies investigating the efficacy of LAG3 inhibition in EAC will also provide predictive evidence and relevance of the immunohistochemical determination of LAG3 expression.


Assuntos
Adenocarcinoma/metabolismo , Antígenos CD/metabolismo , Neoplasias Esofágicas/metabolismo , Linfócitos do Interstício Tumoral/metabolismo , RNA Mensageiro/metabolismo , Adenocarcinoma/patologia , Idoso , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD4-Positivos/patologia , Linfócitos T CD8-Positivos/metabolismo , Linfócitos T CD8-Positivos/patologia , Neoplasias Esofágicas/patologia , Feminino , Humanos , Ativação Linfocitária/fisiologia , Linfócitos do Interstício Tumoral/patologia , Masculino , Estadiamento de Neoplasias/métodos
11.
PLoS One ; 15(6): e0234548, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32542046

RESUMO

BACKGROUND: Myeloid-derived suppressor cells (MDSCs) are potent suppressors of immune function and may play a key role in the development and progression of metastatic cancers. Aerobic exercise has been shown to have anticancer effects, yet the mechanisms behind this protection are largely unknown. Therefore, we examined the effects of physical activity on MDSC accumulation and function. METHODS: Female BALB/c mice were assigned to one of two primary groups: sedentary tumor (SED+TUM) or wheel run tumor (WR+TUM). After 6 weeks of voluntary wheel running, all animals were randomly subdivided into 4 different timepoint groups; 16, 20, 24, and 28 days post-tumor injection. All mice were inoculated with 4T1 mammary carcinoma cells in the mammary fat pad and WR groups continued to run for the specified time post-injection. Spleen, blood, and tumor samples were analyzed using flow cytometry to assess proportions of MDSCs. RESULTS: Cells expressing MDSC biomarkers were detected in the spleen, blood, and tumor beginning at d16. However, since there was no evidence of immunosuppressive function until d28, we refer to them as immature myeloid cells (IMCs). Compared to SED+TUM, levels of IMCs in the spleen were significantly lower (p < 0.05) in WR+TUM at day 16 (33.0 ± 5.2%; 23.1 ± 10.2% of total cells, respectively) and day 20 (33.9 ± 8.1%; 24.3 ± 5.1% of total cells, respectively). Additionally, there were fewer circulating IMCs in WR+TUM at day 16 and MDSC levels were significantly lower (p < 0.05) in the tumor at day 28 in WR+TUM. Additionally, a non-significant 62% and 26% reduction in metastatic lung nodules was observed at days 24 and 28, respectively. At day 28, MDSCs harvested from SED+TUM significantly suppressed CD3+CD4+ T cell proliferation (3.2 ± 1.3 proliferation index) while proliferation in WR+TUM MDSC co-cultures (5.1 ± 1.7 proliferation index) was not different from controls. CONCLUSIONS: These findings suggest that physical activity may delay the accumulation of immunosuppressive MDSCs providing a broader window of opportunity for interventions with immunotherapies.


Assuntos
Imunossupressão , Neoplasias Mamárias Experimentais/metabolismo , Células Supressoras Mieloides/metabolismo , Animais , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Técnicas de Cocultura , Feminino , Imunossupressores/farmacologia , Ativação Linfocitária/genética , Ativação Linfocitária/fisiologia , Neoplasias Mamárias Experimentais/genética , Camundongos , Atividade Motora/genética , Atividade Motora/fisiologia , Células Mieloides/metabolismo , Células Mieloides/patologia , Células Supressoras Mieloides/patologia , Células Supressoras Mieloides/fisiologia
14.
Am J Respir Cell Mol Biol ; 63(2): 255-265, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32320626

RESUMO

Idiopathic pulmonary fibrosis (IPF) is a lethal, medically refractory syndrome characterized by intrapulmonary accumulations of extracellular matrix (ECM) proteins produced by fibroblasts. Activation, clonal expansion, and differentiation of lymphocytes are also frequently present in IPF. Activated T cells are known to exert several effects that promote ECM production, but opposing homeostatic actions, wherein T cells can inhibit fibrosis, are less well understood. We found that CD27, a TNF receptor ubiquitously expressed on naive T cells, is downregulated on CD4 T cells of patients with IPF and that CD70, the sole ligand for CD27, is present on human pulmonary fibroblasts. We hypothesized that cognate engagements between lymphocyte CD27 and fibroblast CD70 could have functional consequences. Accordingly, a series of subsequent studies were conducted to examine the possible role of CD27-CD70 interactions in the regulation of fibrogenesis. Using IB, flow cytometry, RT-PCR, and kinomic assays, we found that fibroblast CD70 expression was inversely correlated with cell density and upregulated by TGF-ß1 (transforming growth factor-ß1). CD70 agonists, including T-cell-derived soluble CD27, markedly diminished fibroblast collagen and fibronectin synthesis, and these effects were potent enough to also inhibit profibrotic actions of TGF-ß1 on ECM production in vitro and in two distinct ex vivo human skin models. CD70 activation was mediated by AKT (protein kinase B) and complex interconnected signaling pathways, and it was abated by prior CD70 knockdown. These results show that the CD70-CD27 axis modulates T-cell-fibroblast interactions and may be an important regulator of fibrosis and wound healing. Fibroblast CD70 could also be a novel target for specific mechanistically based antifibrosis treatments.


Assuntos
Ligante CD27/metabolismo , Proteínas da Matriz Extracelular/metabolismo , Fibroblastos/metabolismo , Pulmão/metabolismo , Diferenciação Celular/fisiologia , Células Cultivadas , Humanos , Fibrose Pulmonar Idiopática/metabolismo , Ativação Linfocitária/fisiologia , Transdução de Sinais/fisiologia , Linfócitos T/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Membro 7 da Superfamília de Receptores de Fatores de Necrose Tumoral/metabolismo , Cicatrização/fisiologia
15.
Horm Metab Res ; 52(4): 228-235, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32268424

RESUMO

Prolactin is known to have immune modulatory effects acting through the prolactin receptor, which is present on a variety of immune cells. Certain chemokines contribute to form the type of T helper (Th) preponderance in the immune response. The objective of this work was to assess if hyperprolactinemia not related to pregnancy is associated with changes in circulating levels of chemokines and other immunological markers. In this cross sectional study, 35 patients with hyperprolactinemia (5 men), and 102 healthy blood donors (19 men) were included. Serum levels of Th1- Th2- and Th17-associated chemokines, C-reactive protein, immunoglobulins, and the B cell attracting chemokine CXCL13 were assessed. The hyperprolactinemic group had significantly higher levels of Th2 associated CCL22 (p=0.022), Th17 associated CXCL1 (p=0.001), B cell attracting CXCL13 (p=0.003), and C-reactive protein (p<0.001) compared to controls, and these proteins were also positively correlated with prolactin levels. While differences in CCL22, CXCL1, CXCL13, and C-reactive protein were present in patients with low or moderate hyperprolactinemia, no differences were observed at high (>3600 mU/l) prolactin levels. To evaluate a possible dose-associated response to prolactin, an in vitro model was used, showing prolactin-induced increase in T-helper cell activation at moderate levels, while activation decreased at higher levels. Hyperprolactinemia seems to have several immunomodulatory effects and was associated with increased levels of chemokines associated with Th2 and Th17 responses and B cell attraction. However, patients with greatly increased prolactin had normal levels of chemokines, and in vitro, high levels of prolactin decreased T-helper cell activation.


Assuntos
Quimiocinas/metabolismo , Hiperprolactinemia/sangue , Hiperprolactinemia/imunologia , Imunomodulação/fisiologia , Prolactina/sangue , Adulto , Biomarcadores/sangue , Proteína C-Reativa/análise , Proteína C-Reativa/metabolismo , Estudos de Casos e Controles , Quimiocina CXCL13/metabolismo , Feminino , Humanos , Imunoglobulinas/análise , Imunoglobulinas/sangue , Ativação Linfocitária/fisiologia , Masculino , Pessoa de Meia-Idade , Células Th1/metabolismo , Células Th17/metabolismo , Células Th2/metabolismo
16.
Med Sci (Paris) ; 36(3): 253-260, 2020 Mar.
Artigo em Francês | MEDLINE | ID: mdl-32228844

RESUMO

Upon priming by dendritic cells, naïve CD4 T lymphocytes are exposed to distinct molecular environments depending on the nature of the pathological stimulus. In response, they mobilize different gene networks that establish lineage-specific developmental programs, and coordinate the acquisition of specific phenotype and functions. Accordingly, CD4 T cells are capable of differentiation into a large variety of functionally-distinct T helper (Th) cell subsets. In this review, we describe the molecular events that control CD4 T cell differentiation at the level of the chromatin. We insist on recent works that have highlighted the key role of H3K9me3-dependent epigenetic mechanisms in the regulation of T cell identity. Interestingly, these pathways shape and control the developmental programs at least in part through the regulation of endogenous retroviruses-derived sequences that have been exapted into cis-regulatory modules of Th genes.


Assuntos
Retrovirus Endógenos/fisiologia , Fenômenos do Sistema Imunológico/fisiologia , Animais , Linfócitos T CD4-Positivos/fisiologia , Diferenciação Celular/genética , Diferenciação Celular/imunologia , Linhagem da Célula/genética , Linhagem da Célula/imunologia , Células Dendríticas/imunologia , Células Dendríticas/fisiologia , Retrovirus Endógenos/genética , Retrovirus Endógenos/imunologia , Epigênese Genética/fisiologia , Humanos , Ativação Linfocitária/fisiologia , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/fisiologia
17.
PLoS One ; 15(2): e0229036, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32084172

RESUMO

LAT molecules defective in ubiquitination have an increased half-life and induce enhanced signaling when expressed in T cells. In this study, we have examined the role of ubiquitination in regulating LAT endocytosis, recycling, and degradation in resting and stimulated T cells. By tracking and comparing plasma membrane-labeled wild type and ubiquitination-resistant 2KR LAT, we find that ubiquitination promotes the degradation of surface LAT in T cells. Activation of T cells increases LAT ubiquitination and promotes trafficking of internalized LAT to lysosomes for degradation. Ubiquitination of LAT does not change internalization rates from the cell surface, but prevents efficient recycling of LAT to the surface of T cells. Our study demonstrates that surface LAT levels are tightly controlled by ubiquitination. LAT in unstimulated cells lacks ubiquitin allowing for increased LAT stability and efficient T cell activation upon TCR triggering; ubiquitination leads to efficient removal of LAT after activation.


Assuntos
Ativação Linfocitária/fisiologia , Ubiquitinação/fisiologia , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Linhagem Celular , Endocitose/fisiologia , Humanos , Immunoblotting , Lisossomos/metabolismo , Microscopia Confocal , Fosforilação/fisiologia , Transdução de Sinais/fisiologia
18.
Expert Opin Biol Ther ; 20(2): 141-150, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31738626

RESUMO

Introduction: The promotion of antitumor response by targeting co-stimulatory B7 superfamily members has become evident to create a new wave of cancer immunotherapy. Inducible Co-Stimulator (ICOS), which is expressed on activated T cells, gained interest in the translational medicine community.Areas covered: We performed an extensive literature review using the keywords 'ICOS' and 'cancer', and the Clinicaltrials.gov database for early phase clinical trials targeting ICOS. In this review, we highlight the dual role of ICOS in oncogenesis in different malignancies. We summarize the current state of knowledge about ICOS/ICOSL pathway targeting by immunotherapies.Expert opinion: Due to its multifaceted link with anti-tumor immunity, both antagonist and agonist antibodies might be of interest to target the ICOS/ICOSL pathway for tumor treatment. Indeed, ICOS activation might potentiate the effect of an inhibitory checkpoint blockade, while its neutralization could decrease the function of immunosuppressive Tregs and inhibit lymphoid tumor cells expressing Tfh markers.


Assuntos
Imunoterapia/métodos , Proteína Coestimuladora de Linfócitos T Induzíveis/fisiologia , Neoplasias/terapia , Animais , Humanos , Tolerância Imunológica/imunologia , Proteína Coestimuladora de Linfócitos T Induzíveis/imunologia , Ativação Linfocitária/fisiologia , Neoplasias/imunologia , Linfócitos T Reguladores/fisiologia
19.
Eur J Immunol ; 50(2): 234-244, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31621896

RESUMO

SOCS3 is a crucial feedback inhibitor of several cytokine pathways with potential regulatory functions during T cell receptor activation. A role of SOCS3 in IL-7-dependent homeostatic mechanisms has been assumed but the underlying mechanisms remain unclear. We investigated the role of SOCS3 in IL-7 receptor α-chain (IL-7Rα) expression and IL-7 effects on activated human CD4+ T cells. SOCS3 expression modulation by lentiviral transduction combined with T cell phenotyping, receptor signalling analysis, and a novel competitive in vitro assay were applied. Time course analyses following T-cell activation showed IL-7Rα re-expression after initial down-regulation that was accompanied by increased SOCS3 expression starting on day 2. T cells with low SOCS3 expression (SOCS3kd ) had decreased IL-7Rα levels due to impaired re-expression. SOCS3 mediated effects on IL-7Rα were not affected by recombinant IL-7 or blocking of IL-2. We found no evidence for SOCS3 effects on IL7RA transcriptional regulation. Functionally, SOCS3kd T cells showed decreased IL-7-dependent proliferation as compared to vector control T cells under competitive in vitro conditions. This impaired IL-7 response of SOCS3kd T cells was accompanied by decreased STAT5 phosphorylation late during IL-7 signalling. We identified a novel SOCS3 function in IL-7Rα regulation during T-cell activation with crucial implications for IL-7-dependent mechanisms.


Assuntos
Proliferação de Células/fisiologia , Interleucina-7/metabolismo , Ativação Linfocitária/fisiologia , Receptores de Interleucina-7/metabolismo , Proteína 3 Supressora da Sinalização de Citocinas/metabolismo , Linfócitos T/metabolismo , Citocinas/metabolismo , Regulação para Baixo/fisiologia , Regulação da Expressão Gênica/fisiologia , Humanos , Transdução de Sinais/fisiologia , Proteínas Supressoras da Sinalização de Citocina/metabolismo
20.
J Exp Med ; 217(1)2020 01 06.
Artigo em Inglês | MEDLINE | ID: mdl-31636135

RESUMO

Follicular helper T (Tfh) cells provide essential help for humoral immune response. Transcriptional factor Bcl6 is the master regulator for Tfh generation and is induced very early after T cell activation in a CD28-dependent manner, but how CD28 signal promotes Bcl6 early expression remains unknown. Here we found that CD28 signal quickly induces expression of the H3K36me2 methytransferase Nsd2, which is required for Bcl6 expression as early as the first cell division after T cell activation. Nsd2 deficiency in T cells leads to decreased Bcl6 expression, impaired Tfh generation, compromised germinal center response, and delayed virus clearance. Ectopic Bcl6 expression rescues the Tfh defect of Nsd2 KO cells. ICOS signal is dispensable for early Nsd2 induction but required for sustained Nsd2 expression, which is critical for Tfh maintenance. Overexpression of Nsd2 increases Bcl6 expression and enhances Tfh generation; 4-mo-old mice even develop spontaneous Tfh. Overall, our study reveals Nsd2 as a critical epigenetic regulator for Tfh differentiation.


Assuntos
Diferenciação Celular/fisiologia , Histona Metiltransferases/metabolismo , Histona-Lisina N-Metiltransferase/metabolismo , Linfócitos T Auxiliares-Indutores/metabolismo , Animais , Feminino , Regulação da Expressão Gênica/fisiologia , Centro Germinativo/metabolismo , Hematopoese/fisiologia , Ativação Linfocitária/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Proteínas Proto-Oncogênicas c-bcl-6/metabolismo , Transdução de Sinais/fisiologia
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