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In the version of this article initially published, the institution name for affiliation 3 (Maryland Anderson Cancer Center) was incorrect. The correct institution is MD Anderson Cancer Center. The error has been corrected in the HTML and PDF versions of the article.
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This corrects the article DOI: 10.1038/ni.3748.
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An imbalance in the lineages of immunosuppressive regulatory T cells (Treg cells) and the inflammatory TH17 subset of helper T cells leads to the development of autoimmune and/or inflammatory disease. Here we found that TAZ, a coactivator of TEAD transcription factors of Hippo signaling, was expressed under TH17 cell-inducing conditions and was required for TH17 differentiation and TH17 cell-mediated inflammatory diseases. TAZ was a critical co-activator of the TH17-defining transcription factor RORγt. In addition, TAZ attenuated Treg cell development by decreasing acetylation of the Treg cell master regulator Foxp3 mediated by the histone acetyltransferase Tip60, which targeted Foxp3 for proteasomal degradation. In contrast, under Treg cell-skewing conditions, TEAD1 expression and sequestration of TAZ from the transcription factors RORγt and Foxp3 promoted Treg cell differentiation. Furthermore, deficiency in TAZ or overexpression of TEAD1 induced Treg cell differentiation, whereas expression of a transgene encoding TAZ or activation of TAZ directed TH17 cell differentiation. Our results demonstrate a pivotal role for TAZ in regulating the differentiation of Treg cells and TH17 cells.
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Proteínas Adaptadoras de Transdução de Sinal/imunologia , Diferenciação Celular/imunologia , Colite/imunologia , Citocinas/imunologia , Encefalomielite Autoimune Experimental/imunologia , Peptídeos e Proteínas de Sinalização Intracelular/imunologia , Linfócitos T Reguladores/imunologia , Células Th17/imunologia , Acetilação , Proteínas Adaptadoras de Transdução de Sinal/genética , Animais , Artrite Reumatoide/imunologia , Estudos de Casos e Controles , Imunoprecipitação da Cromatina , Proteínas de Ligação a DNA/imunologia , Proteínas de Ligação a DNA/metabolismo , Citometria de Fluxo , Fatores de Transcrição Forkhead/imunologia , Fatores de Transcrição Forkhead/metabolismo , Células HEK293 , Células HeLa , Histona Acetiltransferases/metabolismo , Humanos , Immunoblotting , Lisina Acetiltransferase 5 , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Microscopia Confocal , Microscopia de Fluorescência , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/imunologia , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/metabolismo , Complexo de Endopeptidases do Proteassoma/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Fator de Transcrição STAT3/imunologia , Fator de Transcrição STAT3/metabolismo , Síndrome de Sjogren/imunologia , Proteínas Smad/imunologia , Proteínas Smad/metabolismo , Fatores de Transcrição de Domínio TEA , Transativadores/metabolismo , Fatores de Transcrição/imunologia , Fatores de Transcrição/metabolismo , Proteínas com Motivo de Ligação a PDZ com Coativador TranscricionalRESUMO
Follicular helper T cells (T(FH) cells) are responsible for effective B cell-mediated immunity, and Bcl-6 is a central factor for the differentiation of T(FH) cells. However, the molecular mechanisms that regulate the induction of T(FH) cells remain unclear. Here we found that the E3 ubiquitin ligase Itch was essential for the differentiation of T(FH) cells, germinal center responses and immunoglobulin G (IgG) responses to acute viral infection. Itch acted intrinsically in CD4(+) T cells at early stages of T(FH) cell development. Itch seemed to act upstream of Bcl-6 expression, as Bcl-6 expression was substantially impaired in Itch(-/-) cells, and the differentiation of Itch(-/-) T cells into T(FH) cells was restored by enforced expression of Bcl-6. Itch associated with the transcription factor Foxo1 and promoted its ubiquitination and degradation. The defective T(FH) differentiation of Itch(-/-) T cells was rectified by deletion of Foxo1. Thus, our results indicate that Itch acts as an essential positive regulator in the differentiation of T(FH) cells.
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Diferenciação Celular , Linfócitos T Auxiliares-Indutores/citologia , Ubiquitina-Proteína Ligases/fisiologia , Animais , Proteína Forkhead Box O1 , Fatores de Transcrição Forkhead/fisiologia , Centro Germinativo/imunologia , Interleucina-2/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Proto-Oncogênicas c-bcl-6/fisiologia , Células Th2/imunologiaRESUMO
Classical genetic approaches to examine the requirements of genes for T cell differentiation during infection are time consuming. Here we developed a pooled approach to screen 30-100+ genes individually in separate antigen-specific T cells during infection using short hairpin RNAs in a microRNA context (shRNAmir). Independent screens using T cell receptor (TCR)-transgenic CD4(+) and CD8(+) T cells responding to lymphocytic choriomeningitis virus (LCMV) identified multiple genes that regulated development of follicular helper (Tfh) and T helper 1 (Th1) cells, and short-lived effector and memory precursor cytotoxic T lymphocytes (CTLs). Both screens revealed roles for the positive transcription elongation factor (P-TEFb) component Cyclin T1 (Ccnt1). Inhibiting expression of Cyclin T1, or its catalytic partner Cdk9, impaired development of Th1 cells and protective short-lived effector CTL and enhanced Tfh cell and memory precursor CTL formation in vivo. This pooled shRNA screening approach should have utility in numerous immunological studies.
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Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Diferenciação Celular/imunologia , Vírus da Coriomeningite Linfocítica/imunologia , Interferência de RNA/imunologia , Animais , Diferenciação Celular/genética , Ciclina T/biossíntese , Ciclina T/genética , Quinase 9 Dependente de Ciclina/biossíntese , Quinase 9 Dependente de Ciclina/genética , Memória Imunológica/imunologia , Ativação Linfocitária/imunologia , Coriomeningite Linfocítica/imunologia , Camundongos , Camundongos Endogâmicos C57BL , MicroRNAs/genética , Fator 1 de Ligação ao Domínio I Regulador Positivo , RNA Interferente Pequeno , Receptores de Antígenos de Linfócitos T/genética , Proteínas com Domínio T/genética , Linfócitos T Citotóxicos/imunologia , Células Th1/imunologia , Fatores de Transcrição/genética , Transdução Genética/métodosRESUMO
MicroRNAs (miRNAs) are thought to exert their functions by modulating the expression of hundreds of target genes and each to a small degree, but it remains unclear how small changes in hundreds of target genes are translated into the specific function of a miRNA. Here, we conducted an integrated analysis of transcriptome and translatome of primary B cells from mutant mice expressing miR-17~92 at three different levels to address this issue. We found that target genes exhibit differential sensitivity to miRNA suppression and that only a small fraction of target genes are actually suppressed by a given concentration of miRNA under physiological conditions. Transgenic expression and deletion of the same miRNA gene regulate largely distinct sets of target genes. miR-17~92 controls target gene expression mainly through translational repression and 5'UTR plays an important role in regulating target gene sensitivity to miRNA suppression. These findings provide molecular insights into a model in which miRNAs exert their specific functions through a small number of key target genes.
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Linfócitos B/metabolismo , Regulação da Expressão Gênica , MicroRNAs/genética , Biossíntese de Proteínas/genética , Transcriptoma/genética , Regiões 5' não Traduzidas/genética , Animais , Linfócitos B/citologia , Sequência de Bases , Proteína 11 Semelhante a Bcl-2/genética , Proteína 11 Semelhante a Bcl-2/metabolismo , Células Cultivadas , Citometria de Fluxo , Perfilação da Expressão Gênica/métodos , Immunoblotting , Camundongos Knockout , Camundongos Transgênicos , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Receptor do Fator de Crescimento Transformador beta Tipo II , Receptores de Fatores de Crescimento Transformadores beta/genética , Receptores de Fatores de Crescimento Transformadores beta/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Ribossomos/genética , Ribossomos/metabolismoRESUMO
TNFα is a powerful inflammatory stimulus, central both to the control of infection, and as an agent of inflammatory disease. The most potent inducers of TNFα secretion signal through the Toll-like receptors, and we describe here a chemically-induced mutation that impairs this response in macrophages. A missense mutation was revealed in the gene encoding the inactive rhomboid protease iRhom2, which was not complemented by a null allele of the same gene. Neither the missense nor the null allele affected TLR-induced secretion of IL-6. Moreover, unlike a mutation in TNFα, the iRhom2 missense mutation did not cause enhanced susceptibility to colitis induced by dextran sodium sulfate. These results establish a specific role for iRhom2 in the secretion of TNFα, and present a new target for the modulation of inflammation.
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Proteínas de Transporte/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Alelos , Animais , Sequência de Bases , Proteínas de Transporte/genética , Análise Mutacional de DNA , Genes Recessivos/genética , Camundongos , Camundongos Endogâmicos C57BL , Dados de Sequência Molecular , Mutação/genética , Receptores Toll-Like/metabolismoRESUMO
The immune responses during the initiation and invasion stages of human lung adenocarcinoma (LUAD) development are largely unknown. Here, we generated a single-cell RNA sequencing map to decipher the immune dynamics during human LUAD development. We found that T follicular helper (Tfh)-like cells, germinal center B cells, and dysfunctional CD8+ T cells increase during tumor initiation/invasion and form a tertiary lymphoid structure (TLS) inside the tumor. This TLS starts with an aggregation of CD4+ T cells and the generation of CXCL13-expressing Tfh-like cells, followed by an accumulation of B cells, and then forms a CD4+ T and B cell aggregate. TLS and its associated cells are correlated with better patient survival. Inhibiting TLS formation by Tfh or B cell depletion promotes tumor growth in mouse models. The anti-tumoral effect of the Tfh-dependent TLS is mediated through interleukin-21 (IL-21)-IL-21 receptor signaling. Our study establishes an anti-tumoral role of the Tfh-dependent TLS in the development of LUAD.
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Adenocarcinoma de Pulmão , Neoplasias Pulmonares , Estruturas Linfoides Terciárias , Animais , Camundongos , Humanos , Linfócitos T Auxiliares-Indutores , Estruturas Linfoides Terciárias/patologia , Linfócitos T CD8-Positivos/patologiaRESUMO
Programmed death-ligand 1 (PD-L1) is overexpressed in multiple cancers and critical for their immune escape. It has previously shown that the nuclear coactivator SRC-1 promoted colorectal cancer (CRC) progression by enhancing CRC cell viability, yet its role in CRC immune escape is unclear. Here, we demonstrate that SRC-1 is positively correlated with PD-L1 in human CRC specimens. SRC-1 deficiency significantly inhibits PD-L1 expression in CRC cells and retards murine CRC growth in subcutaneous grafts by enhancing CRC immune escape via increasing tumor infiltration of CD8+ T cells. Genetic ablation of SRC-1 in mice also decreases PD-L1 expression in AOM/DSS-induced murine CRC. These results suggest that tumor-derived SRC-1 promotes CRC immune escape by enhancing PD-L1 expression. Mechanistically, SRC-1 activated JAK-STAT signaling by inhibiting SOCS1 expression and coactivated STAT3 and IRF1 to enhance PD-L1 transcription as well as stabilized PD-L1 protein by inhibiting proteasome-dependent degradation mediated by speckle type POZ protein (SPOP). Pharmacological inhibition of SRC-1 improved the antitumor effect of PD-L1 antibody in both subcutaneous graft and AOM/DSS-induced murine CRC models. Taken together, these findings highlight a crucial role of SRC-1 in regulating PD-L1 expression and targeting SRC-1 in combination with PD-L1 antibody immunotherapy may be an attractive strategy for CRC treatment.
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The tumor microenvironment (TME) has a significant impact on tumor growth and immunotherapy efficacies. However, the precise cellular interactions and spatial organizations within the TME that drive these effects remain elusive. Using advanced multiplex imaging techniques, we have discovered that regulatory T cells (Tregs) accumulate around lymphatic vessels in the peripheral tumor stroma. This localized accumulation is facilitated by mature dendritic cells enriched in immunoregulatory molecules (mregDCs), which promote chemotaxis of Tregs, establishing a peri-lymphatic Treg-mregDC niche. Within this niche, mregDCs facilitate Treg activation, which in turn restrains the trafficking of tumor antigens to the draining mesenteric lymph nodes, thereby impeding the initiation of anti-tumor adaptive immune responses. Disrupting Treg recruitment to mregDCs inhibits tumor progression. Our study provides valuable insights into the organization of TME and how local crosstalk between lymphoid and myeloid cells suppresses anti-tumor immune responses.
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Células Dendríticas , Linfócitos T Reguladores , Microambiente Tumoral , Linfócitos T Reguladores/imunologia , Animais , Microambiente Tumoral/imunologia , Camundongos , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Humanos , Antígenos de Neoplasias/imunologia , Antígenos de Neoplasias/metabolismo , Vasos Linfáticos/imunologia , Vasos Linfáticos/metabolismo , Camundongos Endogâmicos C57BL , Linfonodos/imunologia , Linhagem Celular Tumoral , Neoplasias/imunologia , Neoplasias/metabolismoRESUMO
Cellular immunity mediated by CD8+ T cells plays an indispensable role in bacterial and viral clearance and cancers. However, persistent antigen stimulation of CD8+ T cells leads to an exhausted or dysfunctional cellular state characterized by the loss of effector function and high expression of inhibitory receptors during chronic viral infection and in tumors. Numerous studies have shown that glycogen synthase kinase 3 (GSK3) controls the function and development of immune cells, but whether GSK3 affects CD8+ T cells is not clearly elucidated. Here, we demonstrate that mice with deletion of Gsk3α and Gsk3ß in activated CD8+ T cells (DKO) exhibited decreased CTL differentiation and effector function during acute and chronic viral infection. In addition, DKO mice failed to control tumor growth due to the upregulated expression of inhibitory receptors and augmented T-cell exhaustion in tumor-infiltrating CD8+ T cells. Strikingly, anti-PD-1 immunotherapy substantially restored tumor rejection in DKO mice. Mechanistically, GSK3 regulates T-cell exhaustion by suppressing TCR-induced nuclear import of NFAT, thereby in turn dampening NFAT-mediated exhaustion-related gene expression, including TOX/TOX2 and PD-1. Thus, we uncovered the molecular mechanisms underlying GSK3 regulation of CTL differentiation and T-cell exhaustion in anti-tumor immune responses.
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Neoplasias , Viroses , Camundongos , Animais , Linfócitos T CD8-Positivos , Quinase 3 da Glicogênio Sintase/metabolismo , Exaustão das Células T , Diferenciação Celular , Viroses/metabolismoRESUMO
Cerebral malaria (CM) is a severe neurological complication of Plasmodium falciparum infection with acute brain lesions. Genetic variations in both host and parasite have been associated with susceptibility to CM, but the underlying molecular mechanism remains unclear. Here, we demonstrate that variants of human apolipoprotein E (hApoE) impact the outcome of Plasmodium berghei ANKA (PbA)-induced experimental cerebral malaria (ECM). Mice carrying the hApoE2 isoform have fewer intracerebral hemorrhages and are more resistant to ECM than mice bearing the hApoE3, hApoE4, or endogenous murine ApoE (mApoE). hApoE2 mice infected with PbA showed increased splenomegaly and IFN-γ levels in serum but reduced cerebral cell apoptosis that correlated with the survival advantage against ECM. In addition, upregulated expression of genes associated with lipid metabolism and downregulated expression of genes linked to immune responses were observed in the brain tissue of hApoE2 mice relative to ECM-susceptible mice after PbA infection. Notably, serum cholesterol and the cholesterol content of brain-infiltrating CD8+ T cells are significantly higher in infected hApoE2 mice, which might contribute to a significant reduction in the sequestration of brain CD8+ T cells. Consistent with the finding that fewer brain lesions occurred in infected hApoE2 mice, fewer behavioral deficits were observed in the hApoE2 mice. Finally, a meta-analysis of publicly available data also showed an increased hApoE2 allele in the malaria-endemic African population, suggesting malaria selection. This study shows that hApoE2 protects mice from ECM through suppression of CD8+ T cell activation and migration to the brain and enhanced cholesterol metabolism.IMPORTANCECerebral malaria (CM) is the deadliest complication of malaria infection with an estimated 15%-25% mortality. Even with timely and effective treatment with antimalarial drugs such as quinine and artemisinin derivatives, survivors of CM may suffer long-term cognitive and neurological impairment. Here, we show that human apolipoprotein E variant 2 (hApoE2) protects mice from experimental CM (ECM) via suppression of CD8+ T cell activation and infiltration to the brain, enhanced cholesterol metabolism, and increased IFN-γ production, leading to reduced endothelial cell apoptosis, BBB disruption, and ECM symptoms. Our results suggest that hApoE can be an important factor for risk assessment and treatment of CM in humans.
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Type 1 conventional dendritic cells (cDC1) are the most efficient cross-presenting cells that induce protective cytotoxic T cell response. However, the regulation of their homeostasis and function is incompletely understood. Here we observe a selective reduction of splenic cDC1 accompanied by excessive cell death in mice with Zeb1 deficiency in dendritic cells, rendering the mice more resistant to Listeria infection. Additionally, cDC1 from other sources of Zeb1-deficient mice display impaired cross-presentation of exogenous antigens, compromising antitumor CD8+ T cell responses. Mechanistically, Zeb1 represses the expression of microRNA-96/182 that target Cybb mRNA of NADPH oxidase Nox2, and consequently facilitates reactive-oxygen-species-dependent rupture of phagosomal membrane to allow antigen export to the cytosol. Cybb re-expression in Zeb1-deficient cDC1 fully restores the defective cross-presentation while microRNA-96/182 overexpression in Zeb1-sufficient cDC1 inhibits cross-presentation. Therefore, our results identify a Zeb1-microRNA-96/182-Cybb pathway that controls cross-presentation in cDC1 and uncover an essential role of Zeb1 in cDC1 homeostasis.
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MicroRNAs , Fatores de Transcrição , Animais , Camundongos , Antígenos/metabolismo , Linfócitos T CD8-Positivos , Células Dendríticas , Homeostase , MicroRNAs/genética , MicroRNAs/metabolismo , Fatores de Transcrição/metabolismoRESUMO
T helper type 2 (Th2) cytokine-activated M2 macrophages contribute to inflammation resolution and wound healing. This study shows that IL-4-primed macrophages exhibit a stronger response to lipopolysaccharide stimulation while maintaining M2 signature gene expression. Metabolic divergence between canonical M2 and non-canonical proinflammatory-prone M2 (M2INF) macrophages occurs after the IL-4Rα/Stat6 axis. Glycolysis supports Hif-1α stabilization and proinflammatory phenotype of M2INF macrophages. Inhibiting glycolysis blunts Hif-1α accumulation and M2INF phenotype. Wdr5-dependent H3K4me3 mediates the long-lasting effect of IL-4, with Wdr5 knockdown inhibiting M2INF macrophages. Our results also show that the induction of M2INF macrophages by IL-4 intraperitoneal injection and transferring of M2INF macrophages confer a survival advantage against bacterial infection in vivo. In conclusion, our findings highlight the previously neglected non-canonical role of M2INF macrophages and broaden our understanding of IL-4-mediated physiological changes. These results have immediate implications for how Th2-skewed infections could redirect disease progression in response to pathogen infection.
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Interleucina-4 , Macrófagos , Humanos , Interleucina-4/farmacologia , Interleucina-4/metabolismo , Macrófagos/metabolismo , Inflamação/metabolismo , Citocinas/metabolismo , Glicólise/fisiologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismoRESUMO
gC1qR is one of the C1q receptors implicated in the regulation of innate and adaptive immunity. We found that gC1qR inhibits RIG-I and MDA5-dependent antiviral signaling. Double stranded RNA and virus trigger the translocation of gC1qR to the mitochondrial outer membrane leading to the interaction of gC1qR with the RIG-I and MDA5 adaptor, VISA/MAVS/IPS-1/Cardif. The interaction of gC1qR with VISA/MAVS/IPS-1/Cardif at mitochondria results in the disruption of RIG-I and MDA5 signaling and the promotion of virus replication. Knockdown of endogenous gC1qR enhances RIG-I-dependent antiviral signaling, and augments the inhibition of virus proliferation. Therefore, gC1qR is a physiological inhibitor of the RIG-I and MDA5-mediated antiviral signaling pathway. These data uncover a new viral mechanism used to negatively control antiviral signaling in host cells.
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Proteínas de Transporte/fisiologia , RNA Helicases DEAD-box/antagonistas & inibidores , Mitocôndrias/metabolismo , Proteínas Mitocondriais/fisiologia , Viroses/imunologia , Proteínas de Transporte/metabolismo , Linhagem Celular , Proteína DEAD-box 58 , RNA Helicases DEAD-box/metabolismo , Ensaio de Imunoadsorção Enzimática , Técnicas de Silenciamento de Genes , Humanos , Imunidade Inata , Helicase IFIH1 Induzida por Interferon , Proteínas Mitocondriais/metabolismo , Transporte Proteico , Receptores Imunológicos , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transdução de Sinais , Viroses/metabolismoRESUMO
Here, we describe an N-ethyl-N-nitrosourea (ENU)-induced missense error in the membrane-bound transcription factor peptidase site 1 (S1P)-encoding gene (Mbtps1) that causes enhanced susceptibility to dextran sodium sulfate (DSS)-induced colitis. S1P cleaves and activates cAMP response element binding protein/ATF transcription factors, the sterol regulatory element-binding proteins (SREBPs), and other proteins of both endogenous and viral origin. Because S1P has a nonredundant function in the ATF6-dependent unfolded protein response (UPR), woodrat mice show diminished levels of major endoplasmic reticulum chaperones GRP78 (BiP) and GRP94 in the colon upon DSS administration. Experiments with bone marrow chimeric mice reveal a requirement for S1P in nonhematopoietic cells, without which a diminished UPR and colitis develop.
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Fator 6 Ativador da Transcrição/metabolismo , Colite/metabolismo , Serina Endopeptidases/metabolismo , Animais , Colite/induzido quimicamente , Colite/genética , Sulfato de Dextrana/farmacologia , Retículo Endoplasmático/metabolismo , Chaperona BiP do Retículo Endoplasmático , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Mutação/genética , Pró-Proteína Convertases , Dobramento de Proteína , Serina Endopeptidases/genética , Especificidade por SubstratoRESUMO
Programmed death-ligand 1 (PD-L1) is an important immunosuppressive molecule highly expressed on the surface of cancer cells. IFNγ triggered cancer cell immunosuppression against CD8+ T cell surveillance via up-regulation of PD-L1. Histone demethylase JMJD2D promotes colorectal cancer (CRC) progression; however, the role of JMJD2D in cancer immune escape is unknown. Here, we report that both PD-L1 and JMJD2D are frequently overexpressed in human CRC specimens with a significant positive correlation. Genetic ablation of JMJD2D in CRC cells attenuated the expression of PD-L1 and stalled tumor growth in mice, accompanied by the elevated number and effector function of tumor infiltrating CD8+ T cells. Mechanistically, JMJD2D coactivated SP-1 to promote the expression of IFNGR1, which elevated STAT3-IRF1 signaling and promoted PD-L1 expression. Again, JMJD2D is a major coactivator for STAT3-IRF1 axis to enhance PD-L1 transcription in a demethylation activity dependent manner. Furthermore, pharmacological inhibition of JMJD2D conduced to improve the anti-tumor efficacy of PD-L1 antibody as demonstrated by slower tumor growth and higher infiltration and function of CD8+ T cells in the combination of JMJD2D inhibitor 5-c-8HQ and PD-L1 antibody group compared with monotherapy with either agent. These results demonstrate that JMJD2D promotes CRC immune escape by enhancing PD-L1 expression to inhibit the activation and tumor infiltration of CD8+ T cells; targeting JMJD2D has the potential role in promoting the efficacy of anti-PD-1/PD-L1 immunotherapy.
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Antígeno B7-H1 , Neoplasias Colorretais , Histona Desmetilases com o Domínio Jumonji/metabolismo , Animais , Linfócitos T CD8-Positivos , Linhagem Celular Tumoral , Neoplasias Colorretais/patologia , Humanos , Fator Regulador 1 de Interferon/metabolismo , Camundongos , Receptores de Interferon/metabolismo , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais/genética , Receptor de Interferon gamaRESUMO
AIMS: This study was aimed to explore whether sacran polysaccharide has a therapeutic effect on atopic dermatitis (AD) and its possible mechanisms. MATERIALS AND METHODS: 2, 4-dinitrochlorobenzene (DNCB)-induced AD mice were treated with 0.2% Sacran, 0.5% Sacran and 0.1% tacrolimus. Through scoring dermatitis severity, measuring ear thickness, cracking behavior, open field test, we evaluated the therapeutic effect of Sacran on DNCB-induced AD mice. CD4+ T cells and CD8+ T cells were evaluated by flow cytometry. The relative expression of Ifng and Il4 were measured by real-time quantitative PCR. KEY FINDINGS: Sacran could relieved the symptoms of DNCB-induced AD mice, such as AD score, ear thickness, and IgE release. Sacran may alleviate dermatitis by inhibiting Th2 activation and reducing IgE release. SIGNIFICANCE: Our research further proved that polysaccharide Sacran has anti-dermatitis effects, and also clarified its mechanism of alleviating dermatitis by inhibiting the activation of Th2 cells and reducing the release of IgE, which provides a theoretical basis for the future clinical transformation of polysaccharide Sacran.
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Dermatite Atópica/tratamento farmacológico , Dinitroclorobenzeno/toxicidade , Imunoglobulina E/metabolismo , Inflamação/prevenção & controle , Polissacarídeos/farmacologia , Células Th2/imunologia , Animais , Dermatite Atópica/induzido quimicamente , Dermatite Atópica/imunologia , Dermatite Atópica/patologia , Feminino , Indicadores e Reagentes/toxicidade , Inflamação/etiologia , Camundongos , Camundongos Endogâmicos BALB C , Células Th2/efeitos dos fármacosRESUMO
Aberrant expression of Myc is one of the most common oncogenic events in human cancers. Scores of Myc inhibitors are currently under development for treating Myc-driven cancers. In addition to directly targeting tumor cells, Myc inhibition has been shown to modulate the tumor microenvironment to promote tumor regression. However, the effect of Myc inhibition on immune cells in the tumor microenvironment remains poorly understood. Here, we show that the adaptive immune system plays a vital role in the antitumor effect of pharmacologic inhibition of Myc. Combining genetic and pharmacologic approaches, we found that Myc inhibition enhanced CD8 T cell function by suppressing the homeostasis of regulatory T (Treg) cells and the differentiation of resting Treg (rTreg) cells to activated Treg (aTreg) cells in tumors. Importantly, we demonstrated that different Myc expression levels confer differential sensitivity of T cell subsets to pharmacologic inhibition of Myc. Although ablation of the Myc gene has been shown to suppress CD8 T cell function, Treg cells, which express much less Myc protein than CD8 T cells, are more sensitive to Myc inhibitors. The differential sensitivity of CD8 T and Treg cells to Myc inhibitors resulted in enhanced CD8 T cell function upon Myc inhibition. Our findings revealed that Myc inhibitors can induce an antitumor immune response during tumor progression.
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Neoplasias , Linfócitos T Reguladores , Linfócitos T CD8-Positivos , Humanos , Subpopulações de Linfócitos T , Microambiente TumoralRESUMO
Sluggish was identified in a population of third generation mice descended from N-ethyl-N-nitrosourea-mutagenized sires. Macrophages from homozygotes exhibited impaired TNF-alpha production in response to all TLR ligands tested and displayed impaired type I IFN production in response to TLR7 and TLR9 stimulations. The phenotype was confined to a critical region on mouse chromosome 18 and then ascribed to a T to A transversion in the acceptor splice site of intron 4 at position 13346 of the Map3k8 gene, resulting in defective splicing. The Map3k8(Sluggish) mutation does not result in susceptibility to viral infections, but Sluggish mice displayed high susceptibility to group B streptococcus infection, with impaired TNF-alpha and type I IFN production in infected macrophages. Our data demonstrate that the encoded protein kinase Tpl2 plays an essential role in cell signaling in the immune response to certain pathogens.