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1.
Anticancer Res ; 39(9): 4687-4698, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31519568

RESUMO

BACKGROUND/AIM: Propagermanium (PG) inhibits the CCL2/CCR2 axis, and has been shown to function as an immune modulator. This study investigated its anti-tumor mechanism in patients with refractory cancers. MATERIALS AND METHODS: Five healthy volunteers and 23 patients with refractory oral (n=8) or gastric (n=15) cancer received PG (30 mg/day). We performed flow cytometry (FCM) of peripheral blood mononuclear cells and in vitro killing assays. RESULTS: FCM revealed that CD16+/CD56Dim NK cells (i.e., mature, cytolytic subset) increased, and the apoptosis induction rate of cancer cells increased after PG administration. Among gastric cancer patients, median OS was 172.0 days. Two patients showed complete remission of lung or liver metastasis. Survival of patients with oral cancer also tended to be prolonged. CONCLUSION: PG induces NK cell maturation, and may potentiate anti-tumor activity.


Assuntos
Antineoplásicos/farmacologia , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/imunologia , Células Matadoras Naturais/efeitos dos fármacos , Células Matadoras Naturais/imunologia , Neoplasias/imunologia , Neoplasias/mortalidade , Compostos Organometálicos/farmacologia , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos , Humanos , Estimativa de Kaplan-Meier , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/imunologia , Leucócitos Mononucleares/metabolismo , Subpopulações de Linfócitos/imunologia , Subpopulações de Linfócitos/metabolismo , Neoplasias/diagnóstico , Neoplasias/tratamento farmacológico , Tomografia Computadorizada por Raios X
2.
Transplant Proc ; 51(6): 2136-2140, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31399190

RESUMO

A regulatory T (Treg) cell/T helper 17 (Th17) cell imbalance is involved in many autoimmune diseases. Rapamycin (Rapa), a clinically used immunosuppressive drug, has been shown to inhibit Th17 cell differentiation but promote Treg cell generation. In this study, we aimed to study the mechanism of Rapa acting on Treg and Th17 cell differentiation. Purified mouse CD4+CD25- T cells were stimulated and polarized in vitro to generate Th17 or Treg cells in the presence or absence of Rapa. We first confirmed that Rapa inhibited the differentiation of Th17 cells and greatly promoted Treg cell generation in vitro. As metabolic pathways play a key role in T cell differentiation, we then detected the metabolic programs in Rapa-treated T cells. We found that Rapa blocked glycolysis in induced Th17 cells, evidenced by reduced glucose uptake, and inhibited expression of glucose transporter 1 and the rate-limiting enzyme HK2. In addition, the expression of c-Myc and of HIF-1α transcription factor, which regulate many genes involved in glycolysis, were inhibited by Rapa. Conversely, Rapa promoted fatty acid oxidation (FAO) metabolism in differentiated Treg cells, with the elevation of FAO product ß-hydroxybutyrate, and increased expression of ATGL and CPT1A, the key enzymes of FAO in differentiated Treg cells. The expression of phospho-AMPKα, the key signal in the regulation of FAO, was also promoted in Rapa-treated induced Treg cells. Together, these findings indicated that Rapa abrogated glycolysis in Th17 cells but facilitated FAO in induced Treg cells, which may underlie the mechanism by which Rapa regulates the Treg/Th17 balance.


Assuntos
Diferenciação Celular/efeitos dos fármacos , Imunossupressores/farmacologia , Sirolimo/farmacologia , Linfócitos T Reguladores/efeitos dos fármacos , Células Th17/efeitos dos fármacos , Animais , Diferenciação Celular/imunologia , Ativação Linfocitária/efeitos dos fármacos , Ativação Linfocitária/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Linfócitos T Reguladores/imunologia , Células Th17/imunologia
3.
Nat Immunol ; 20(9): 1174-1185, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31406377

RESUMO

Classical type 1 dendritic cells (cDC1s) are required for antiviral and antitumor immunity, which necessitates an understanding of their development. Development of the cDC1 progenitor requires an E-protein-dependent enhancer located 41 kilobases downstream of the transcription start site of the transcription factor Irf8 (+41-kb Irf8 enhancer), but its maturation instead requires the Batf3-dependent +32-kb Irf8 enhancer. To understand this switch, we performed single-cell RNA sequencing of the common dendritic cell progenitor (CDP) and identified a cluster of cells that expressed transcription factors that influence cDC1 development, such as Nfil3, Id2 and Zeb2. Genetic epistasis among these factors revealed that Nfil3 expression is required for the transition from Zeb2hi and Id2lo CDPs to Zeb2lo and Id2hi CDPs, which represent the earliest committed cDC1 progenitors. This genetic circuit blocks E-protein activity to exclude plasmacytoid dendritic cell potential and explains the switch in Irf8 enhancer usage during cDC1 development.


Assuntos
Fatores de Transcrição de Zíper de Leucina Básica/metabolismo , Células Dendríticas/citologia , Elementos Facilitadores Genéticos/genética , Proteína 2 Inibidora de Diferenciação/metabolismo , Fatores Reguladores de Interferon/metabolismo , Homeobox 2 de Ligação a E-box com Dedos de Zinco/metabolismo , Animais , Diferenciação Celular/imunologia , Células Cultivadas , Regulação da Expressão Gênica no Desenvolvimento/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas Repressoras/metabolismo , Células-Tronco/citologia
5.
Nat Immunol ; 20(9): 1244-1255, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31431722

RESUMO

Mucosal-associated invariant T cells (MAIT cells) recognize the microbial metabolite 5-(2-oxopropylideneamino)-6-D-ribitylaminouracil (5-OP-RU) presented by the MHC class Ib molecule, MR1. MAIT cells acquire effector functions during thymic development, but the mechanisms involved are unclear. Here we used single-cell RNA-sequencing to characterize the developmental path of 5-OP-RU-specific thymocytes. In addition to the known MAIT1 and MAIT17 effector subsets selected on bone-marrow-derived hematopoietic cells, we identified 5-OP-RU-specific thymocytes that were selected on thymic epithelial cells and differentiated into CD44- naive T cells. MAIT cell positive selection required signaling through the adapter, SAP, that controlled the expression of the transcription factor, ZBTB16. Pseudotemporal ordering of single cells revealed transcriptional trajectories of 5-OP-RU-specific thymocytes selected on either thymic epithelial cells or hematopoietic cells. The resulting model illustrates T cell lineage decisions.


Assuntos
Linhagem da Célula/imunologia , Células T Invariáveis Associadas à Mucosa/citologia , Células T Invariáveis Associadas à Mucosa/imunologia , Timócitos/citologia , Timócitos/imunologia , Animais , Sequência de Bases , Diferenciação Celular/genética , Diferenciação Celular/imunologia , Antígenos de Histocompatibilidade Classe I/metabolismo , Receptores de Hialuronatos/metabolismo , Ativação Linfocitária/imunologia , Camundongos , Camundongos Knockout , Antígenos de Histocompatibilidade Menor/metabolismo , Proteína com Dedos de Zinco da Leucemia Promielocítica/biossíntese , Receptores de Antígenos de Linfócitos T alfa-beta/imunologia , Análise de Sequência de RNA , Família de Moléculas de Sinalização da Ativação Linfocitária/metabolismo , Timo/citologia , Timo/imunologia
6.
Nat Immunol ; 20(8): 1012-1022, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31263276

RESUMO

The plasma membrane tetraspan molecule MS4A4A is selectively expressed by macrophage-lineage cells, but its function is unknown. Here we report that MS4A4A was restricted to murine and human mononuclear phagocytes and was induced during monocyte-to-macrophage differentiation in the presence of interleukin 4 or dexamethasone. Human MS4A4A was co-expressed with M2/M2-like molecules in subsets of normal tissue-resident macrophages, infiltrating macrophages from inflamed synovium and tumor-associated macrophages. MS4A4A interacted and colocalized with the ß-glucan receptor dectin-1 in lipid rafts. In response to dectin-1 ligands, Ms4a4a-deficient macrophages showed defective signaling and defective production of effector molecules. In experimental models of tumor progression and metastasis, Ms4a4a deficiency in macrophages had no impact on primary tumor growth, but was essential for dectin-1-mediated activation of macrophages and natural killer (NK) cell-mediated metastasis control. Thus, MS4A4A is a tetraspan molecule selectively expressed in macrophages during differentiation and polarization, essential for dectin-1-dependent activation of NK cell-mediated resistance to metastasis.


Assuntos
Células Matadoras Naturais/imunologia , Lectinas Tipo C/metabolismo , Macrófagos/imunologia , Proteínas de Membrana/metabolismo , Metástase Neoplásica/imunologia , Neoplasias/imunologia , Animais , Diferenciação Celular/imunologia , Linhagem da Célula , Dexametasona/farmacologia , Humanos , Interleucina-4/metabolismo , Ativação Linfocitária/imunologia , Ativação de Macrófagos/imunologia , Macrófagos/citologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , Metástase Neoplásica/prevenção & controle , Neoplasias/patologia
7.
APMIS ; 127(9): 642-652, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31274210

RESUMO

Hepatitis C virus (HCV) infection always leads to chronic hepatitis via dysregulation of host immunity. Notch signaling also modulates the response of monocytes/macrophages. Thus, we aimed to investigate the regulatory role of Notch signaling to CD14+ monocytes. Forty patients with chronic hepatitis C and twenty normal controls (NC) were enrolled. CD14+ monocytes and CD4+ T cells were purified from peripheral bloods. Notch receptors' mRNA expression in CD14+ monocytes was semi-quantified by real-time PCR. Cytokine production by CD14+ monocytes in response to γ-secretase inhibitor (GSI) was investigated by ELISA. GSI-induced CD14+ monocytes activity to HCV clearance in Huh7.5 cells and to CD4+ T cell differentiation was also assessed in direct and indirect contact co-culture system. Notch1 mRNA relative level was approximately 10-fold elevated in CD14+ monocytes from chronic hepatitis C patients when compared with NC. GSI stimulation resulted in enhanced cytokines production by CD14+ monocytes from chronic hepatitis C patients. GSI-stimulated CD14+ monocytes from chronic hepatitis C patients induced suppression of HCV RNA replication in both direct and indirect contact co-culture system of CD14+ monocytes and HCVcc-infected Huh7.5 cells, and this process was accompanied by elevation of interferon-γ production but not increased target cell death. Moreover, GSI stimulation also enhanced CD14+ monocytes-induced Th1 and Th17 cells activation, and this process required direct cell-to-cell contact. Effective antiviral therapy down-regulated Notch1 mRNA expression and promoted cytokine production by CD14+ monocytes from chronic hepatitis C. Current data revealed an important immunoregulatory property of Notch signaling to CD14+ monocytes in chronic HCV infection.


Assuntos
Hepatite C Crônica/imunologia , Monócitos/imunologia , Receptor Notch1/imunologia , Transdução de Sinais/imunologia , Adulto , Linfócitos T CD4-Positivos , Diferenciação Celular/imunologia , Técnicas de Cocultura , Regulação para Baixo/imunologia , Feminino , Hepacivirus/imunologia , Humanos , Ativação Linfocitária/imunologia , Masculino , Pessoa de Meia-Idade , Células Th1/imunologia , Células Th17/imunologia , Adulto Jovem
8.
Cancer Sci ; 110(9): 2700-2710, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31276257

RESUMO

As one of the most frequently diagnosed cancers, esophageal squamous cell carcinoma (ESCC) remains the leading cause of malignancy-related death worldwide. Many studies have focused on the potential role of cancer cells in educating B cells during cancer progression. Here, we aim to explore the role of circulating exosomes from ESCC in the generation of two main regulatory B (Breg) subsets, including interleukin-10+ Bregs (B10) and programmed cell death (PD)-1high Bregs. Firstly, we observed an elevated percentage of B10 cells in peripheral blood of ESCC patients compared with healthy controls. Then we isolated and characterized exosomes from the peripheral blood of ESCC patients and an ESCC cell line. Exosomes from ESCC patients and the ESCC cell line suppressed the proliferation of B cells and induced the augmentation of B10 and PD-1high Breg cells. By comparing the long non-coding RNA and mRNA expression profiles in exosomes from ESCC patients or healthy controls, we identified a series of differentially expressed genes. Finally, we undertook gene annotation and pathway enrichment analyses on differentially expressed genes to explore the potential mechanism underlying the modulatory role of cancer exosomes in B cells. Our findings contribute to the study on B cell-mediated ESCC immunosuppression and shed light on the possible application of exosomes in anticancer therapies.


Assuntos
Linfócitos B Reguladores/imunologia , Neoplasias Esofágicas/imunologia , Carcinoma de Células Escamosas do Esôfago/imunologia , Exossomos/imunologia , Linfócitos B Reguladores/metabolismo , Diferenciação Celular/imunologia , Terapia Baseada em Transplante de Células e Tecidos/métodos , Neoplasias Esofágicas/sangue , Neoplasias Esofágicas/terapia , Carcinoma de Células Escamosas do Esôfago/sangue , Carcinoma de Células Escamosas do Esôfago/terapia , Exossomos/transplante , Feminino , Humanos , Interleucina-10/metabolismo , Masculino , Pessoa de Meia-Idade , Receptor de Morte Celular Programada 1/metabolismo
9.
Nat Immunol ; 20(9): 1150-1160, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31358996

RESUMO

Innate lymphoid cells (ILCs) play important functions in immunity and tissue homeostasis, but their development is poorly understood. Through the use of single-cell approaches, we examined the transcriptional and functional heterogeneity of ILC progenitors, and studied the precursor-product relationships that link the subsets identified. This analysis identified two successive stages of ILC development within T cell factor 1-positive (TCF-1+) early innate lymphoid progenitors (EILPs), which we named 'specified EILPs' and 'committed EILPs'. Specified EILPs generated dendritic cells, whereas this potential was greatly decreased in committed EILPs. TCF-1 was dispensable for the generation of specified EILPs, but required for the generation of committed EILPs. TCF-1 used a pre-existing regulatory landscape established in upstream lymphoid precursors to bind chromatin in EILPs. Our results provide insight into the mechanisms by which TCF-1 promotes developmental progression of ILC precursors, while constraining their dendritic cell lineage potential and enforcing commitment to ILC fate.


Assuntos
Linhagem da Célula/imunologia , Células Dendríticas/citologia , Fator 1-alfa Nuclear de Hepatócito/imunologia , Células Progenitoras Linfoides/citologia , Linfócitos T/citologia , Animais , Diferenciação Celular/imunologia , Células Cultivadas , Regulação da Expressão Gênica/genética , Fator 1-alfa Nuclear de Hepatócito/genética , Camundongos , Camundongos Endogâmicos C57BL , Transcrição Genética/genética
10.
Mol Immunol ; 112: 312-321, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31229844

RESUMO

Precise glycosylation plays a crucial and distinctive role in thymic T cell development. The core fucosylation is dramatically up-regulated at the transition from CD4-CD8- (DN) to CD4+CD8+ (DP) in the thymic development. Ablation of core fucosylation in T cells did reduce the size of the thymus due to a significant loss of CD4+ SP, CD8+ SP and DP thymocytes in core fucosyltransferase (Fut8) knockout (Fut8-/-) mice. T cell receptors (TCRs) are heavily core fucosylated glycoproteins. Loss of core fucosylation of TCR contributed to the reduced phosphorylation of ZAP70 (pZAP70) in Fut8-/- DP cells was observed. Compare to the Fut8+/+OT-II DP thymocytes, pZAP70 was significantly reduced in Fut8-/- OT-II DP thymocytes with OVA323-339 stimulation. Also, the pZAP70 of Fut8+/+OT-I DP thymocytes with OVA257-264 stimulation was remarkably attenuated by treatment of the fucosidase. Upon anti-CD3/CD28 Abs stimulation, the increased apoptosis was found in Fut8-/- thymocytes compared with Fut8+/+ thymocytes. Moreover, the TCRhiCD69hi (post-positive selection thymocytes) was markedly depleted in the Fut8-/- thymus without any stimulation. The expression of CD5 was significantly down-regulated on the DP cells in the Fut8-/- thymus. Our results therefore demonstrate that ablation of core fucosylation results in the abnormal T cell development due to the attenuated signaling via TCR.


Assuntos
Fucose/imunologia , Receptores de Antígenos de Linfócitos T/imunologia , Transdução de Sinais/imunologia , Linfócitos T/imunologia , Animais , Antígenos CD/imunologia , Antígenos de Diferenciação de Linfócitos T/imunologia , Apoptose/imunologia , Antígenos CD5/imunologia , Diferenciação Celular/imunologia , Fucosiltransferases/imunologia , Glicosilação , Lectinas Tipo C/imunologia , Ativação Linfocitária/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Fosforilação/imunologia , Timócitos/imunologia , Proteína-Tirosina Quinase ZAP-70/imunologia
11.
Nat Immunol ; 20(8): 1046-1058, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31209405

RESUMO

The neonatal thymus generates Foxp3+ regulatory T (tTreg) cells that are critical in controlling immune homeostasis and preventing multiorgan autoimmunity. The role of antigen specificity on neonatal tTreg cell selection is unresolved. Here we identify 17 self-peptides recognized by neonatal tTreg cells, and reveal ligand specificity patterns that include self-antigens presented in an age- and inflammation-dependent manner. Fate-mapping studies of neonatal peptidyl arginine deiminase type IV (Padi4)-specific thymocytes reveal disparate fate choices. Neonatal thymocytes expressing T cell receptors that engage IAb-Padi4 with moderate dwell times within a conventional docking orientation are exported as tTreg cells. In contrast, Padi4-specific T cell receptors with short dwell times are expressed on CD4+ T cells, while long dwell times induce negative selection. Temporally, Padi4-specific thymocytes are subject to a developmental stage-specific change in negative selection, which precludes tTreg cell development. Thus, a temporal switch in negative selection and ligand binding kinetics constrains the neonatal tTreg selection window.


Assuntos
Autoantígenos/imunologia , Receptores de Antígenos de Linfócitos T alfa-beta/imunologia , Tolerância a Antígenos Próprios/imunologia , Linfócitos T Reguladores/citologia , Animais , Autoimunidade/imunologia , Diferenciação Celular/imunologia , Linhagem Celular , Feminino , Fatores de Transcrição Forkhead/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Linfócitos T Reguladores/imunologia , Timo/citologia
12.
Nat Immunol ; 20(8): 980-991, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31209406

RESUMO

Innate lymphoid cells (ILCs) are tissue-resident lymphocytes categorized on the basis of their core regulatory programs and the expression of signature cytokines. Human ILC3s that produce the cytokine interleukin-22 convert into ILC1-like cells that produce interferon-γ in vitro, but whether this conversion occurs in vivo remains unclear. In the present study we found that ILC3s and ILC1s in human tonsils represented the ends of a spectrum that included additional discrete subsets. RNA velocity analysis identified an intermediate ILC3-ILC1 cluster, which had strong directionality toward ILC1s. In humanized mice, the acquisition of ILC1 features by ILC3s showed tissue dependency. Chromatin studies indicated that the transcription factors Aiolos and T-bet cooperated to repress regulatory elements active in ILC3s. A transitional ILC3-ILC1 population was also detected in the human intestine. We conclude that ILC3s undergo conversion into ILC1-like cells in human tissues in vivo, and that tissue factors and Aiolos were required for this process.


Assuntos
Imunidade Inata/imunologia , Interferon gama/metabolismo , Interleucinas/metabolismo , Mucosa Intestinal/imunologia , Linfócitos/imunologia , Tonsila Palatina/imunologia , Animais , Diferenciação Celular/imunologia , Células Cultivadas , Criança , Pré-Escolar , Humanos , Fator de Transcrição Ikaros/metabolismo , Mucosa Intestinal/citologia , Linfócitos/classificação , Linfócitos/citologia , Camundongos , Proteínas com Domínio T/metabolismo
13.
Nat Immunol ; 20(7): 879-889, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31182807

RESUMO

CD8+ T cells and natural killer (NK) cells are central cellular components of immune responses against pathogens and cancer, which rely on interleukin (IL)-15 for homeostasis. Here we show that IL-15 also mediates homeostatic priming of CD8+ T cells for antigen-stimulated activation, which is controlled by a deubiquitinase, Otub1. IL-15 mediates membrane recruitment of Otub1, which inhibits ubiquitin-dependent activation of AKT, a kinase that is pivotal for T cell activation and metabolism. Otub1 deficiency in mice causes aberrant responses of CD8+ T cells to IL-15, rendering naive CD8+ T cells hypersensitive to antigen stimulation characterized by enhanced metabolic reprograming and effector functions. Otub1 also controls the maturation and activation of NK cells. Deletion of Otub1 profoundly enhances anticancer immunity by unleashing the activity of CD8+ T cells and NK cells. These findings suggest that Otub1 controls the activation of CD8+ T cells and NK cells by functioning as a checkpoint of IL-15-mediated priming.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Cisteína Endopeptidases/metabolismo , Interleucina-15/metabolismo , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/metabolismo , Ativação Linfocitária/genética , Ativação Linfocitária/imunologia , Animais , Diferenciação Celular/genética , Diferenciação Celular/imunologia , Cisteína Endopeptidases/deficiência , Enzimas Desubiquitinantes/metabolismo , Modelos Animais de Doenças , Metabolismo Energético , Interações Hospedeiro-Patógeno/genética , Interações Hospedeiro-Patógeno/imunologia , Humanos , Interleucina-15/genética , Melanoma Experimental , Camundongos , Camundongos Transgênicos , Ligação Proteica , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptores de Interleucina-15/metabolismo , Tolerância a Antígenos Próprios/genética , Tolerância a Antígenos Próprios/imunologia , Transdução de Sinais , Especificidade do Receptor de Antígeno de Linfócitos T , Ubiquitinação
14.
Immunity ; 50(6): 1482-1497.e7, 2019 06 18.
Artigo em Inglês | MEDLINE | ID: mdl-31201094

RESUMO

The skin comprises tissue macrophages as the most abundant resident immune cell type. Their diverse tasks including resistance against invading pathogens, attraction of bypassing immune cells from vessels, and tissue repair require dynamic specification. Here, we delineated the postnatal development of dermal macrophages and their differentiation into subsets by adapting single-cell transcriptomics, fate mapping, and imaging. Thereby we identified a phenotypically and transcriptionally distinct subset of prenatally seeded dermal macrophages that self-maintained with very low postnatal exchange by hematopoietic stem cells. These macrophages specifically interacted with sensory nerves and surveilled and trimmed the myelin sheath. Overall, resident dermal macrophages contributed to axon sprouting after mechanical injury. In summary, our data show long-lasting functional specification of macrophages in the dermis that is driven by stepwise adaptation to guiding structures and ensures codevelopment of ontogenetically distinct cells within the same compartment.


Assuntos
Diferenciação Celular/imunologia , Vigilância Imunológica , Macrófagos/imunologia , Regeneração Nervosa , Pele/imunologia , Pele/inervação , Animais , Animais Recém-Nascidos , Biomarcadores , Receptor 1 de Quimiocina CX3C/metabolismo , Derme/citologia , Derme/imunologia , Derme/metabolismo , Imunofenotipagem , Macrófagos/metabolismo , Camundongos , Pele/citologia
15.
Life Sci ; 231: 116536, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31176785

RESUMO

AIMS: TL1A was reported to contribute to the susceptibility to ulcerative colitis (UC). However, the molecular mechanisms of TL1A in UC development are poorly understood. We aimed to investigate the role of TL1A in colitis, and reveal the regulatory mechanism of TL1A in chronic colitis development. MAIN METHODS: Wild-type mice and transgenic mice with overexpressing TL1A in lymphocytes were used to construct chronic DSS colitis models. To investigate the molecular mechanism in vitro, CD4+ T cells were sorted from spleens and mesenteric lymph node cells to induce Th9 cells. Biopsy specimens from ulcerative colitis patients were collected for in vivo validation. KEY FINDINGS: The elevated TL1A expression in chronic DSS colitis models exacerbated intestinal inflammation. The differentiation of Th9 cells, IL-9 secretion and production of TGF-ß, IL-4 and PU.1 was significantly enhanced in transgenic mice with TL1A overexpression. In vitro results showed that TL1A enhanced the Th9 cells, IL-9 and PU.1 production, while TL1A antibodies inhibited their production. In human translational studies, patients with ulcerative colitis with elevated TL1A expression also exhibited more serious inflammation with higher levels of Th9 cells, IL-9 and PU.1 expression. SIGNIFICANCE: We presented a possible mechanism of TL1A in UC development that TL1A may promote the differentiation of Th9 cells and enhanced IL-9 secretion by up-regulating the expression of TGF-ß, IL-4 and PU.1, which provided a novel perspective to study the UC pathogenesis, and indicated that targeting of TL1A signal pathway may by a likely strategy for the treatment of chronic colitis.


Assuntos
Colite/imunologia , Interleucina-9/imunologia , Linfócitos T/imunologia , Membro 15 da Superfamília de Ligantes de Fatores de Necrose Tumoral/imunologia , Animais , Diferenciação Celular/imunologia , Colite/induzido quimicamente , Colite/patologia , Citocinas/imunologia , Citocinas/metabolismo , Glutationa/metabolismo , Interleucina-17/imunologia , Interleucina-1beta/metabolismo , Interleucina-9/metabolismo , Mucosa Intestinal/imunologia , Intestinos/imunologia , Intestinos/patologia , Ativação Linfocitária , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Transdução de Sinais , Subpopulações de Linfócitos T/imunologia , Fator de Crescimento Transformador beta/imunologia , Membro 15 da Superfamília de Ligantes de Fatores de Necrose Tumoral/biossíntese , Fator de Necrose Tumoral alfa/metabolismo
16.
Nat Immunol ; 20(7): 852-864, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31213723

RESUMO

Dendritic cells (DC) are currently classified as conventional DCs (cDCs) and plasmacytoid DCs (pDCs). Through a combination of single-cell transcriptomic analysis, mass cytometry, in vivo fate mapping and in vitro clonal assays, here we show that, at the single-cell level, the priming of mouse hematopoietic progenitor cells toward the pDC lineage occurs at the common lymphoid progenitor stage, indicative of early divergence of the pDC and cDC lineages. We found the transcriptional signature of a pDC precursor stage, defined here, in the IL-7Rα+ common lymphoid progenitor population and identified Ly6D, IL-7Rα, CD81 and CD2 as key markers of pDC differentiation, which distinguish pDC precursors from cDC precursors. In conclusion, pDCs developed in the bone marrow from a Ly6DhiCD2hi lymphoid progenitor cell and differentiated independently of the myeloid cDC lineage.


Assuntos
Antígenos Ly/metabolismo , Células Dendríticas/citologia , Células Dendríticas/metabolismo , Células Progenitoras Linfoides/citologia , Células Progenitoras Linfoides/metabolismo , Células Progenitoras Mieloides/citologia , Células Progenitoras Mieloides/metabolismo , Animais , Linfócitos B/imunologia , Linfócitos B/metabolismo , Biomarcadores , Células da Medula Óssea/citologia , Células da Medula Óssea/metabolismo , Diferenciação Celular/genética , Diferenciação Celular/imunologia , Citometria de Fluxo , Proteínas Ligadas por GPI/metabolismo , Expressão Gênica , Perfilação da Expressão Gênica , Camundongos , Transcriptoma
17.
Nature ; 571(7764): 270-274, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31207604

RESUMO

Tumour-specific CD8 T cell dysfunction is a differentiation state that is distinct from the functional effector or memory T cell states1-6. Here we identify the nuclear factor TOX as a crucial regulator of the differentiation of tumour-specific T (TST) cells. We show that TOX is highly expressed in dysfunctional TST cells from tumours and in exhausted T cells during chronic viral infection. Expression of TOX is driven by chronic T cell receptor stimulation and NFAT activation. Ectopic expression of TOX in effector T cells in vitro induced a transcriptional program associated with T cell exhaustion. Conversely, deletion of Tox in TST cells in tumours abrogated the exhaustion program: Tox-deleted TST cells did not upregulate genes for inhibitory receptors (such as Pdcd1, Entpd1, Havcr2, Cd244 and Tigit), the chromatin of which remained largely inaccessible, and retained high expression of transcription factors such as TCF-1. Despite their normal, 'non-exhausted' immunophenotype, Tox-deleted TST cells remained dysfunctional, which suggests that the regulation of expression of inhibitory receptors is uncoupled from the loss of effector function. Notably, although Tox-deleted CD8 T cells differentiated normally to effector and memory states in response to acute infection, Tox-deleted TST cells failed to persist in tumours. We hypothesize that the TOX-induced exhaustion program serves to prevent the overstimulation of T cells and activation-induced cell death in settings of chronic antigen stimulation such as cancer.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/patologia , Diferenciação Celular/imunologia , Proteínas de Grupo de Alta Mobilidade/metabolismo , Proteínas de Homeodomínio/metabolismo , Neoplasias/imunologia , Animais , Linfócitos T CD8-Positivos/citologia , Linfócitos T CD8-Positivos/metabolismo , Epigênese Genética , Regulação Neoplásica da Expressão Gênica , Proteínas de Grupo de Alta Mobilidade/deficiência , Proteínas de Grupo de Alta Mobilidade/genética , Proteínas de Homeodomínio/genética , Humanos , Memória Imunológica , Linfócitos do Interstício Tumoral/citologia , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Linfócitos do Interstício Tumoral/patologia , Camundongos , Neoplasias/patologia , Fenótipo , Receptores de Antígenos de Linfócitos T/imunologia , Transcrição Genética
18.
Immunity ; 50(5): 1132-1148, 2019 05 21.
Artigo em Inglês | MEDLINE | ID: mdl-31117010

RESUMO

Helping B cells and antibody responses is a major function of CD4+ T cells. It has been 10 years since the publication of Bcl6 as the lineage-defining transcription factor for T follicular helper (Tfh) differentiation and the requirement of Tfh cells as the specialized subset of CD4+ T cells needed for germinal centers (the microanatomical sites of B cell mutation and antibody affinity maturation) and related B cell responses. A great deal has been learned about Tfh cells in the past 10 years, particularly regarding their roles in a surprising range of diseases. Advances in the understanding of Tfh cell differentiation and function are discussed, as are the understanding of Tfh cells in infectious diseases, vaccines, autoimmune diseases, allergies, atherosclerosis, organ transplants, and cancer. This includes discussion of Tfh cells in the human immune system. Based on the discoveries to date, the next decade of Tfh research surely holds many more surprises. VIDEO ABSTRACT.


Assuntos
Linfócitos B/imunologia , Centro Germinativo/imunologia , Linfócitos T Auxiliares-Indutores/citologia , Linfócitos T Auxiliares-Indutores/imunologia , Aterosclerose/imunologia , Doenças Autoimunes/imunologia , Diferenciação Celular/imunologia , Doenças Transmissíveis/imunologia , Humanos , Hipersensibilidade/imunologia , Proteínas Proto-Oncogênicas c-bcl-6/metabolismo
19.
Immunity ; 50(5): 1172-1187.e7, 2019 05 21.
Artigo em Inglês | MEDLINE | ID: mdl-31076359

RESUMO

Although viral infections elicit robust interferon-γ (IFN-γ) and long-lived antibody-secreting cell (ASC) responses, the roles for IFN-γ and IFN-γ-induced transcription factors (TFs) in ASC development are unclear. We showed that B cell intrinsic expression of IFN-γR and the IFN-γ-induced TF T-bet were required for T-helper 1 cell-induced differentiation of B cells into ASCs. IFN-γR signaling induced Blimp1 expression in B cells but also initiated an inflammatory gene program that, if not restrained, prevented ASC formation. T-bet did not affect Blimp1 upregulation in IFN-γ-activated B cells but instead regulated chromatin accessibility within the Ifng and Ifngr2 loci and repressed the IFN-γ-induced inflammatory gene program. Consistent with this, B cell intrinsic T-bet was required for formation of long-lived ASCs and secondary ASCs following viral, but not nematode, infection. Therefore, T-bet facilitates differentiation of IFN-γ-activated inflammatory effector B cells into ASCs in the setting of IFN-γ-, but not IL-4-, induced inflammatory responses.


Assuntos
Linfócitos B/imunologia , Interferon gama/imunologia , Receptores de Interferon/metabolismo , Proteínas com Domínio T/metabolismo , Linfócitos T Auxiliares-Indutores/imunologia , Animais , Células Produtoras de Anticorpos/imunologia , Linfócitos B/citologia , Diferenciação Celular/imunologia , Células Cultivadas , Cromatina/metabolismo , Vírus da Influenza A Subtipo H1N1/imunologia , Vírus da Influenza A Subtipo H3N2/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Nematospiroides dubius/imunologia , Infecções por Orthomyxoviridae/imunologia , Infecções por Orthomyxoviridae/virologia , Fator 1 de Ligação ao Domínio I Regulador Positivo/biossíntese , Infecções por Strongylida/imunologia , Infecções por Strongylida/parasitologia , Proteínas com Domínio T/genética
20.
Mol Immunol ; 112: 115-122, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31082645

RESUMO

Mycobacterium tuberculosis (M. tuberculosis) persistent infection might cause the dysfunction of hematopoiesis. To investigate whether M. tuberculosis persistent antigen stimulation impairs the proliferation and differentiation of hematopoietic stem and progenitor cells characterized as lineage- c-Kit+ (LK cells), C57BL/6 mice were primed with Mycobacterium bovis Bacillus Calmette-Guérin (BCG) and boosted with a cocktail of M. tuberculosis antigens ESAT6, CFP10 and Mtb10.4-HspX (MH) along with adjuvant N, N'-dimethyl-N, N'-dioctadecylammonium bromide (DDA) plus polyinosinic-polycytidylic acid (Poly I:C) weekly for 12 or 22 weeks. The cytokine production by splenic T cells, proliferation of LK cells and transcriptional events during differentiation of bone marrow (BM) c-Kit+ cells were investigated. Meanwhile, the mice were treated with interleukin 2 (IL-2) and the therapeutic effects were analyzed. We found that antigen specific interferon-γ (IFN-γ) production by splenic CD4+ T cells increased following antigen stimulation for 12 weeks, but it declined after continuous stimulation for 22 weeks. The long-term exposure of mice to M. tuberculosis antigen compromised the proliferation of LK cells. Moreover, the expression of transcription factors in the c-Kit+ cells was adjusted, with up-regulation of IRF8 and Batf2 involved in myeloid differentiation and down-regulation of NOTCH1 and GATA2 participated in T-cell lineage commitment. The concentrations of IFN-γ in BM of the persistent antigen group were higher than that in sham control at the 12th week, while the concentrations of IL-2 in BM of the persistent antigen group were lower compared with the transient antigen stimulation control. Following IL-2 treatment, the concentrations of IL-2 in BM increased while IFN-γ got declined. IL-2 treatment could restore the expression levels of those transcription factors and the proliferating activity of LK cells impaired by persistent antigen stimulation. Our results indicate that M. tuberculosis antigen persistent stimulation decreases the proliferating activity of LK cells, promotes myelopoietic differentiation, and represses lymphopoietic differentiation as a consequence of elevated IFN-γ production. IL-2 supplementation contributes to maintaining the homeostasis of hemopoiesis.


Assuntos
Antígenos de Bactérias/imunologia , Medula Óssea/imunologia , Proliferação de Células/fisiologia , Mycobacterium tuberculosis/imunologia , Transcrição Genética/imunologia , Adjuvantes Imunológicos/farmacologia , Animais , Anticorpos Antibacterianos/imunologia , Proteínas de Bactérias/imunologia , Medula Óssea/microbiologia , Linfócitos T CD4-Positivos/imunologia , Diferenciação Celular/imunologia , Feminino , Transplante de Células-Tronco Hematopoéticas/métodos , Interferon gama/imunologia , Interleucina-2/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Mycobacterium bovis/imunologia , Fatores de Transcrição/imunologia
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