RESUMO
The immune system has evolved to mount an effective defense against pathogens and to minimize deleterious immune-mediated inflammation caused by commensal microorganisms, immune responses against self and environmental antigens, and metabolic inflammatory disorders. Regulatory T (Treg) cell-mediated suppression serves as a vital mechanism of negative regulation of immune-mediated inflammation and features prominently in autoimmune and autoinflammatory disorders, allergy, acute and chronic infections, cancer, and metabolic inflammation. The discovery that Foxp3 is the transcription factor that specifies the Treg cell lineage facilitated recent progress in understanding the biology of regulatory T cells. In this review, we discuss cellular and molecular mechanisms in the differentiation and function of these cells.
Assuntos
Linfócitos T Reguladores/imunologia , Animais , Diferenciação Celular , Citocinas/imunologia , Citocinas/metabolismo , Ativação Enzimática , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/metabolismo , Regulação da Expressão Gênica , Homeostase/imunologia , Humanos , Tolerância Imunológica , MicroRNAs/imunologia , MicroRNAs/metabolismo , Ligação Proteica , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptores de Antígenos de Linfócitos T/imunologia , Receptores de Antígenos de Linfócitos T/metabolismo , Transdução de Sinais , Linfócitos T Reguladores/citologia , Linfócitos T Reguladores/metabolismo , Timo/imunologia , Timo/metabolismo , Transcrição GênicaRESUMO
Numerous microRNAs and their target mRNAs are coexpressed across diverse cell types. However, it is unknown whether they are regulated in a manner independent of or dependent on cellular context. Here, we explored transcriptome-wide targeting and gene regulation by miR-155, whose activation-induced expression plays important roles in innate and adaptive immunity. Through mapping of miR-155 targets through differential iCLIP, mRNA quantification with RNA-seq, and 3' untranslated region (UTR)-usage analysis with poly(A)-seq in macrophages, dendritic cells, and T and B lymphocytes either sufficient or deficient in activated miR-155, we identified numerous targets differentially bound by miR-155. Whereas alternative cleavage and polyadenylation (ApA) contributed to differential miR-155 binding to some transcripts, in most cases, identical 3'-UTR isoforms were differentially regulated across cell types, thus suggesting ApA-independent and cellular-context-dependent miR-155-mediated gene regulation. Our study provides comprehensive maps of miR-155 regulatory networks and offers a valuable resource for dissecting context-dependent and context-independent miRNA-mediated gene regulation in key immune cell types.
Assuntos
Linfócitos B/imunologia , Células Dendríticas/imunologia , Regulação da Expressão Gênica/imunologia , Macrófagos/imunologia , MicroRNAs/imunologia , Linfócitos T/imunologia , Animais , Camundongos , Camundongos Endogâmicos C57BL , Camundongos KnockoutRESUMO
During infection, antigen-specific T cells undergo tightly regulated developmental transitions controlled by transcriptional and post-transcriptional regulation of gene expression. We found that the microRNA miR-31 was strongly induced by activation of the T cell antigen receptor (TCR) in a pathway involving calcium and activation of the transcription factor NFAT. During chronic infection with lymphocytic choriomeningitis virus (LCMV) clone 13, miR-31-deficent mice recovered from clinical disease, while wild-type mice continued to show signs of disease. This disease phenotype was explained by the presence of larger numbers of cytokine-secreting LCMV-specific CD8+ T cells in miR-31-deficent mice than in wild-type mice. Mechanistically, miR-31 increased the sensitivity of T cells to type I interferons, which interfered with effector T cell function and increased the expression of several proteins related to T cell dysfunction during chronic infection. These studies identify miR-31 as an important regulator of T cell exhaustion in chronic infection.
Assuntos
Infecções por Arenaviridae/imunologia , Linfócitos T CD8-Positivos/imunologia , Citocinas/imunologia , MicroRNAs/imunologia , Receptores de Antígenos de Linfócitos T/imunologia , Animais , Anticorpos Antivirais/imunologia , Infecções por Arenaviridae/genética , Linfócitos T CD8-Positivos/efeitos dos fármacos , Cálcio/metabolismo , Imunoprecipitação da Cromatina , Células Dendríticas/imunologia , Ensaio de Imunoadsorção Enzimática , Citometria de Fluxo , Perfilação da Expressão Gênica , Immunoblotting , Interferon Tipo I/farmacologia , Vírus da Coriomeningite Linfocítica/imunologia , Camundongos , Camundongos Knockout , MicroRNAs/genética , Fatores de Transcrição NFATC/metabolismo , Reação em Cadeia da Polimerase em Tempo RealRESUMO
Type I interferons (IFNs) are critical cytokines in the host defense against invading pathogens. Sustained production of IFNs, however, is detrimental to the host, as it provokes autoimmune diseases. Thus, the expression of IFNs is tightly controlled. We report that the mRNA 5' cap-binding protein 4EHP plays a key role in regulating type I IFN concomitant with controlling virus replication, both in vitro and in vivo. Mechanistically, 4EHP suppresses IFN-ß production by effecting the miR-34a-induced translational silencing of Ifnb1 mRNA. miR-34a is upregulated by both RNA virus infection and IFN-ß induction, prompting a negative feedback regulatory mechanism that represses IFN-ß expression via 4EHP. These findings demonstrate the direct involvement of 4EHP in virus-induced host response, underscoring a critical translational silencing mechanism mediated by 4EHP and miR-34a to impede sustained IFN production. This study highlights an intrinsic regulatory function for miRNA and the translation machinery in maintaining host homeostasis.
Assuntos
Fator de Iniciação 4E em Eucariotos/imunologia , Imunidade Inata , MicroRNAs/imunologia , Biossíntese de Proteínas/imunologia , Infecções por Vírus de RNA/imunologia , Vírus de RNA/imunologia , Animais , Fator de Iniciação 4E em Eucariotos/genética , Células HEK293 , Humanos , Interferon beta/genética , Interferon beta/imunologia , Camundongos , Camundongos Transgênicos , MicroRNAs/genética , Infecções por Vírus de RNA/genética , Vírus de RNA/genéticaRESUMO
Autoreactive B cells have critical roles in a large diversity of autoimmune diseases, but the molecular pathways that control these cells remain poorly understood. We performed an in vivo functional screen of a lymphocyte-expressed microRNA library and identified miR-148a as a potent regulator of B cell tolerance. Elevated miR-148a expression impaired B cell tolerance by promoting the survival of immature B cells after engagement of the B cell antigen receptor by suppressing the expression of the autoimmune suppressor Gadd45α, the tumor suppressor PTEN and the pro-apoptotic protein Bim. Furthermore, increased expression of miR-148a, which occurs frequently in patients with lupus and lupus-prone mice, facilitated the development of lethal autoimmune disease in a mouse model of lupus. Our studies demonstrate a function for miR-148a as a regulator of B cell tolerance and autoimmunity.
Assuntos
Apoptose/genética , Autoimunidade/genética , Linfócitos B/imunologia , Tolerância Imunológica/genética , MicroRNAs/genética , Animais , Apoptose/imunologia , Proteínas Reguladoras de Apoptose/metabolismo , Autoimunidade/imunologia , Proteína 11 Semelhante a Bcl-2 , Transplante de Medula Óssea , Proteínas de Ciclo Celular/metabolismo , Proliferação de Células/genética , Modelos Animais de Doenças , Células HEK293 , Humanos , Tolerância Imunológica/imunologia , Immunoblotting , Lúpus Eritematoso Sistêmico/imunologia , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos MRL lpr , MicroRNAs/imunologia , Proteínas Nucleares/metabolismo , PTEN Fosfo-Hidrolase/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Análise de Sequência de RNARESUMO
Natural killer (NK) cells are cytotoxic type 1 innate lymphoid cells (ILCs) that defend against viruses and mediate anti-tumor responses, yet mechanisms controlling their development and function remain incompletely understood. We hypothesized that the abundantly expressed microRNA-142 (miR-142) is a critical regulator of type 1 ILC biology. Interleukin-15 (IL-15) signaling induced miR-142 expression, whereas global and ILC-specific miR-142-deficient mice exhibited a cell-intrinsic loss of NK cells. Death of NK cells resulted from diminished IL-15 receptor signaling within miR-142-deficient mice, likely via reduced suppressor of cytokine signaling-1 (Socs1) regulation by miR-142-5p. ILCs persisting in Mir142-/- mice demonstrated increased expression of the miR-142-3p target αV integrin, which supported their survival. Global miR-142-deficient mice exhibited an expansion of ILC1-like cells concurrent with increased transforming growth factor-ß (TGF-ß) signaling. Further, miR-142-deficient mice had reduced NK-cell-dependent function and increased susceptibility to murine cytomegalovirus (MCMV) infection. Thus, miR-142 critically integrates environmental cues for proper type 1 ILC homeostasis and defense against viral infection.
Assuntos
Homeostase/imunologia , Imunidade Inata/imunologia , Linfócitos/imunologia , MicroRNAs/imunologia , Animais , Linhagem Celular , Feminino , Células HEK293 , Humanos , Células Matadoras Naturais/imunologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Muromegalovirus/imunologia , Células NIH 3T3 , Receptores de Interleucina-15/imunologia , Transdução de Sinais/imunologia , Proteínas Supressoras da Sinalização de Citocina/imunologia , Fator de Crescimento Transformador beta/imunologiaRESUMO
MicroRNAs (miRNAs) exert powerful effects on immunological function by tuning networks of target genes that orchestrate cell activity. We sought to identify miRNAs and miRNA-regulated pathways that control the type 2 helper T cell (TH2 cell) responses that drive pathogenic inflammation in asthma. Profiling miRNA expression in human airway-infiltrating T cells revealed elevated expression of the miRNA miR-19a in asthma. Modulating miR-19 activity altered TH2 cytokine production in both human and mouse T cells, and TH2 cell responses were markedly impaired in cells lacking the entire miR-17â¼92 cluster. miR-19 promoted TH2 cytokine production and amplified inflammatory signaling by direct targeting of the inositol phosphatase PTEN, the signaling inhibitor SOCS1 and the deubiquitinase A20. Thus, upregulation of miR-19a in asthma may be an indicator and a cause of increased TH2 cytokine production in the airways.
Assuntos
Asma/imunologia , Citocinas/biossíntese , MicroRNAs/imunologia , Células Th2/imunologia , Animais , Asma/genética , Asma/metabolismo , Líquido da Lavagem Broncoalveolar/citologia , Ensaios Clínicos como Assunto , Citometria de Fluxo , Ensaios de Triagem em Larga Escala , Humanos , Inflamação/genética , Inflamação/imunologia , Inflamação/metabolismo , Camundongos , Camundongos Transgênicos , Reação em Cadeia da Polimerase Multiplex , Células Th2/metabolismo , Regulação para CimaRESUMO
miR-126 is a microRNA expressed predominately by endothelial cells and controls angiogenesis. We found miR-126 was required for the innate response to pathogen-associated nucleic acids and that miR-126-deficient mice had greater susceptibility to infection with pseudotyped HIV. Profiling of miRNA indicated that miR-126 had high and specific expression by plasmacytoid dendritic cells (pDCs). Moreover, miR-126 controlled the survival and function of pDCs and regulated the expression of genes encoding molecules involved in the innate response, including Tlr7, Tlr9 and Nfkb1, as well as Kdr, which encodes the growth factor receptor VEGFR2. Deletion of Kdr in DCs resulted in reduced production of type I interferon, which supports the proposal of a role for VEGFR2 in miR-126 regulation of pDCs. Our studies identify the miR-126-VEGFR2 axis as an important regulator of the innate response that operates through multiscale control of pDCs.
Assuntos
Células Dendríticas/imunologia , Imunidade Inata/imunologia , MicroRNAs/imunologia , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/imunologia , Animais , Células Dendríticas/metabolismo , Citometria de Fluxo , Infecções por HIV/imunologia , Infecções por HIV/virologia , Humanos , Imunidade Inata/genética , Immunoblotting , Interferon-alfa/sangue , Interferon-alfa/imunologia , Interferon-alfa/metabolismo , Camundongos , Camundongos Knockout , Camundongos Transgênicos , MicroRNAs/genética , MicroRNAs/metabolismo , Subunidade p50 de NF-kappa B/genética , Subunidade p50 de NF-kappa B/imunologia , Subunidade p50 de NF-kappa B/metabolismo , Ácidos Nucleicos/imunologia , Ácidos Nucleicos/metabolismo , Oligodesoxirribonucleotídeos/genética , Oligodesoxirribonucleotídeos/imunologia , Análise de Sequência com Séries de Oligonucleotídeos , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Receptor 7 Toll-Like/genética , Receptor 7 Toll-Like/imunologia , Receptor 7 Toll-Like/metabolismo , Receptor Toll-Like 9/genética , Receptor Toll-Like 9/imunologia , Receptor Toll-Like 9/metabolismo , Transcriptoma/imunologia , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/genética , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismoRESUMO
Roquin proteins preclude spontaneous T cell activation and aberrant differentiation of T follicular helper (Tfh) or T helper 17 (Th17) cells. Here we showed that deletion of Roquin-encoding alleles specifically in regulatory T (Treg) cells also caused the activation of conventional T cells. Roquin-deficient Treg cells downregulated CD25, acquired a follicular Treg (Tfr) cell phenotype, and suppressed germinal center reactions but could not protect from colitis. Roquin inhibited the PI3K-mTOR signaling pathway by upregulation of Pten through interfering with miR-17â¼92 binding to an overlapping cis-element in the Pten 3' UTR, and downregulated the Foxo1-specific E3 ubiquitin ligase Itch. Loss of Roquin enhanced Akt-mTOR signaling and protein synthesis, whereas inhibition of PI3K or mTOR in Roquin-deficient T cells corrected enhanced Tfh and Th17 or reduced iTreg cell differentiation. Thereby, Roquin-mediated control of PI3K-mTOR signaling prevents autoimmunity by restraining activation and differentiation of conventional T cells and specialization of Treg cells.
Assuntos
Colite/imunologia , Fosfatidilinositol 3-Quinases/imunologia , Proteínas Repressoras/imunologia , Serina-Treonina Quinases TOR/imunologia , Ubiquitina-Proteína Ligases/imunologia , Animais , Linfócitos B/imunologia , Linfócitos B/patologia , Diferenciação Celular , Colite/genética , Colite/patologia , Modelos Animais de Doenças , Feminino , Proteína Forkhead Box O1/genética , Proteína Forkhead Box O1/imunologia , Regulação da Expressão Gênica , Centro Germinativo/imunologia , Centro Germinativo/patologia , Subunidade alfa de Receptor de Interleucina-2/genética , Subunidade alfa de Receptor de Interleucina-2/imunologia , Ativação Linfocitária , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , MicroRNAs/genética , MicroRNAs/imunologia , PTEN Fosfo-Hidrolase/genética , PTEN Fosfo-Hidrolase/imunologia , Fosfatidilinositol 3-Quinases/genética , Cultura Primária de Células , Proteínas Repressoras/deficiência , Proteínas Repressoras/genética , Transdução de Sinais , Baço/imunologia , Baço/patologia , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/patologia , Serina-Treonina Quinases TOR/genética , Células Th17/imunologia , Células Th17/patologia , Ubiquitina-Proteína Ligases/deficiência , Ubiquitina-Proteína Ligases/genéticaRESUMO
Transforming growth factor beta (TGF-ß) signaling is essential for a balanced immune response by mediating the development and function of regulatory T cells (Tregs) and suppressing autoreactive T cells. Disruption of this balance can result in autoimmune diseases, including multiple sclerosis (MS). MicroRNAs (miRNAs) targeting TGF-ß signaling have been shown to be upregulated in naïve CD4 T cells in MS patients, resulting in a limited in vitro generation of human Tregs. Utilizing the murine model experimental autoimmune encephalomyelitis, we show that perinatal administration of miRNAs, which target the TGF-ß signaling pathway, enhanced susceptibility to central nervous system (CNS) autoimmunity. Neonatal mice administered with these miRNAs further exhibited reduced Treg frequencies with a loss in T cell receptor repertoire diversity following the induction of experimental autoimmune encephalomyelitis in adulthood. Exacerbated CNS autoimmunity as a result of miRNA overexpression in CD4 T cells was accompanied by enhanced Th1 and Th17 cell frequencies. These findings demonstrate that increased levels of TGF-ß-associated miRNAs impede the development of a diverse Treg population, leading to enhanced effector cell activity, and contributing to an increased susceptibility to CNS autoimmunity. Thus, TGF-ß-targeting miRNAs could be a risk factor for MS, and recovering optimal TGF-ß signaling may restore immune homeostasis in MS patients.
Assuntos
Autoimunidade , Sistema Nervoso Central , Encefalomielite Autoimune Experimental , MicroRNAs , Esclerose Múltipla , Transdução de Sinais , Linfócitos T Reguladores , Células Th17 , Fator de Crescimento Transformador beta , MicroRNAs/genética , MicroRNAs/imunologia , Animais , Linfócitos T Reguladores/imunologia , Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/genética , Fator de Crescimento Transformador beta/metabolismo , Camundongos , Transdução de Sinais/imunologia , Autoimunidade/imunologia , Esclerose Múltipla/imunologia , Esclerose Múltipla/genética , Humanos , Sistema Nervoso Central/imunologia , Células Th17/imunologia , Camundongos Endogâmicos C57BL , Células Th1/imunologia , Diferenciação Celular/imunologia , FemininoRESUMO
Standard definitions of immunological memory are all built on the idea that once infected, animals are protected more efficiently against a second infection. This common view overlooks an unavoidable consequence of the exposure of cells to pathogens, danger signals and environmental agents in general: stimuli change cell properties and activity in a transient yet sustained manner that extends beyond the exposure time and modulates the response of cells of both the innate and adaptive immune systems to secondary stimulation. We suggest that this transient phenomenon represents 'short-term memory' of environmental exposure and discuss the evidence that this is mediated by the persistence of long-lived regulatory molecules, notably a subset of newly deposited chromatin modifications and inducible noncoding RNAs.
Assuntos
Cromatina/imunologia , Exposição Ambiental , Memória Imunológica/imunologia , Memória de Curto Prazo/fisiologia , MicroRNAs/imunologia , Imunidade Adaptativa/genética , Imunidade Adaptativa/imunologia , Cromatina/genética , Humanos , Imunidade Inata/genética , Imunidade Inata/imunologia , Memória Imunológica/genética , MicroRNAs/genéticaRESUMO
Follicular helper T cells (TFH cells) are the prototypic helper T cell subset specialized to enable B cells to form germinal centers (GCs) and produce high-affinity antibodies. We found that expression of microRNAs (miRNAs) by T cells was essential for TFH cell differentiation. More specifically, we show that after immunization of mice with protein, the miRNA cluster miR-17â¼92 was critical for robust differentiation and function of TFH cells in a cell-intrinsic manner that occurred regardless of changes in proliferation. In a viral infection model, miR-17â¼92 restrained the expression of genes 'inappropriate' to the TFH cell subset, including the direct miR-17â¼92 target Rora. Removal of one Rora allele partially 'rescued' the inappropriate gene signature in miR-17â¼92-deficient TFH cells. Our results identify the miR-17â¼92 cluster as a critical regulator of T cell-dependent antibody responses, TFH cell differentiation and the fidelity of the TFH cell gene-expression program.
Assuntos
Diferenciação Celular/imunologia , Regulação da Expressão Gênica/imunologia , MicroRNAs/imunologia , Membro 1 do Grupo F da Subfamília 1 de Receptores Nucleares/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Imunidade Adaptativa/imunologia , Animais , Infecções por Arenaviridae/imunologia , Infecções por Arenaviridae/virologia , Citometria de Fluxo , Imuno-Histoquímica , Vírus da Coriomeningite Linfocítica/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Membro 1 do Grupo F da Subfamília 1 de Receptores Nucleares/genética , Estatísticas não Paramétricas , Linfócitos T Auxiliares-Indutores/citologiaRESUMO
Follicular helper T cells (T(FH) cells) provide critical help to B cells during humoral immune responses. Here we report that mice with T cell-specific deletion of the miR-17â¼92 family of microRNAs (miRNAs) had substantially compromised T(FH) differentiation, germinal-center formation and antibody responses and failed to control chronic viral infection. Conversely, mice with T cell-specific expression of a transgene encoding miR-17â¼92 spontaneously accumulated T(FH) cells and developed a fatal immunopathology. Mechanistically, the miR-17â¼92 family controlled the migration of CD4(+) T cells into B cell follicles by regulating signaling intensity from the inducible costimulator ICOS and kinase PI(3)K by suppressing expression of the phosphatase PHLPP2. Our findings demonstrate an essential role for the miR-17â¼92 family in T(FH) differentiation and establish PHLPP2 as an important mediator of their function in this process.
Assuntos
Linfócitos B/imunologia , Diferenciação Celular/imunologia , Centro Germinativo/imunologia , MicroRNAs/imunologia , Proteínas Nucleares/imunologia , Fosfoproteínas Fosfatases/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Animais , Citometria de Fluxo , Centro Germinativo/citologia , Imunidade Humoral/imunologia , Imuno-Histoquímica , Proteína Coestimuladora de Linfócitos T Induzíveis/imunologia , Coriomeningite Linfocítica/imunologia , Coriomeningite Linfocítica/virologia , Vírus da Coriomeningite Linfocítica/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Fosfatidilinositol 3-Quinases/imunologia , Transdução de Sinais/imunologia , Organismos Livres de Patógenos Específicos , Linfócitos T Auxiliares-Indutores/citologia , Linfócitos T Auxiliares-Indutores/enzimologiaRESUMO
We found upregulation of expression of the microRNA miR-155 in primary effector and effector memory CD8(+) T cells, but low miR-155 expression in naive and central memory cells. Antiviral CD8(+) T cell responses and viral clearance were impaired in miR-155-deficient mice, and this defect was intrinsic to CD8(+) T cells, as miR-155-deficient CD8(+) T cells mounted greatly diminished primary and memory responses. Conversely, miR-155 overexpression augmented antiviral CD8(+) T cell responses in vivo. Gene-expression profiling showed that miR-155-deficient CD8(+) T cells had enhanced type I interferon signaling and were more susceptible to interferon's antiproliferative effect. Inhibition of the type I interferon-associated transcription factors STAT1 or IRF7 resulted in enhanced responses of miR-155-deficient CD8(+) T cells in vivo. We have thus identified a previously unknown role for miR-155 in regulating responsiveness to interferon and CD8(+) T cell responses to pathogens in vivo.
Assuntos
Linfócitos T CD8-Positivos/imunologia , Interferons/imunologia , MicroRNAs/imunologia , Transdução de Sinais/imunologia , Animais , Linfócitos T CD8-Positivos/metabolismo , Proliferação de Células/efeitos dos fármacos , Citometria de Fluxo , Perfilação da Expressão Gênica , Redes Reguladoras de Genes/genética , Redes Reguladoras de Genes/imunologia , Immunoblotting , Memória Imunológica/genética , Memória Imunológica/imunologia , Fator Regulador 7 de Interferon/genética , Fator Regulador 7 de Interferon/imunologia , Fator Regulador 7 de Interferon/metabolismo , Interferons/metabolismo , Interferons/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , MicroRNAs/genética , MicroRNAs/metabolismo , Análise de Sequência com Séries de Oligonucleotídeos , Orthomyxoviridae/imunologia , Infecções por Orthomyxoviridae/genética , Infecções por Orthomyxoviridae/imunologia , Infecções por Orthomyxoviridae/virologia , Interferência de RNA , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fator de Transcrição STAT1/genética , Fator de Transcrição STAT1/imunologia , Fator de Transcrição STAT1/metabolismo , Transdução de Sinais/genética , Proteína 1 Supressora da Sinalização de Citocina , Proteínas Supressoras da Sinalização de Citocina/genética , Proteínas Supressoras da Sinalização de Citocina/imunologia , Proteínas Supressoras da Sinalização de Citocina/metabolismoRESUMO
Like the story of Jekyll and Hyde, Th17 cells have two guises. One helps with host immunity, but the other can cause immunopathology. In this issue of Immunity, Dong and colleagues report that three microRNAs, miR-183, miR-96, and miR-182, can enhance the pathogenicity of Th17 cells (Ichiyama et al., 2016).
Assuntos
MicroRNAs/imunologia , Células Th17/imunologia , HumanosRESUMO
Regulatory T (Treg) cells are critical in preventing aberrant immune responses. Posttranscriptional control of gene expression by microRNA (miRNA) has recently emerged as an essential genetic element for Treg cell function. Here, we report that mice with Treg cell-specific ablation of miR-142 (hereafter Foxp3CremiR-142fl/fl mice) developed a fatal systemic autoimmune disorder due to a breakdown in peripheral T-cell tolerance. Foxp3CremiR-142fl/fl mice displayed a significant decrease in the abundance and suppressive capacity of Treg cells. Expression profiling of miR-142-deficient Treg cells revealed an up-regulation of multiple genes in the interferon gamma (IFNγ) signaling network. We identified several of these IFNγ-associated genes as direct miR-142-3p targets and observed excessive IFNγ production and signaling in miR-142-deficient Treg cells. Ifng ablation rescued the Treg cell homeostatic defect and alleviated development of autoimmunity in Foxp3CremiR-142fl/fl mice. Thus, our findings implicate miR-142 as an indispensable regulator of Treg cell homeostasis that exerts its function by attenuating IFNγ responses.
Assuntos
Autoimunidade/imunologia , Regulação da Expressão Gênica/imunologia , Homeostase/imunologia , MicroRNAs/imunologia , Linfócitos T Reguladores/imunologia , Doença Aguda , Animais , Autoimunidade/genética , Transplante de Medula Óssea/métodos , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/imunologia , Fatores de Transcrição Forkhead/metabolismo , Perfilação da Expressão Gênica/métodos , Doença Enxerto-Hospedeiro/imunologia , Homeostase/genética , Interferon gama/genética , Interferon gama/imunologia , Interferon gama/metabolismo , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , MicroRNAs/genética , RNA-Seq/métodos , Transdução de Sinais/genética , Linfócitos T Reguladores/metabolismoRESUMO
Distinct CD4(+) T cell subsets are critical for host defense and immunoregulation. Although these subsets can act as terminally differentiated lineages, they have been increasingly noted to demonstrated plasticity. MicroRNAs are factors that control T cell stability and plasticity. Here we report that naturally occurring regulatory T cells (T(reg) cells) had high expression of the microRNA miR-10a and that miR-10a was induced by retinoic acid and transforming growth factor-ß (TGF-ß) in inducible T(reg) cells. By simultaneously targeting the transcriptional repressor Bcl-6 and the corepressor Ncor2, miR-10a attenuated the phenotypic conversion of inducible T(reg) cells into follicular helper T cells. We also found that miR-10a limited differentiation into the T(H)17 subset of helper T cells and therefore represents a factor that can fine-tune the plasticity and fate of helper T cells.
Assuntos
MicroRNAs/biossíntese , Proteínas Proto-Oncogênicas c-bcl-6/metabolismo , Linfócitos T Auxiliares-Indutores/efeitos dos fármacos , Linfócitos T Reguladores/efeitos dos fármacos , Fator de Crescimento Transformador beta/farmacologia , Tretinoína/farmacologia , Animais , Diferenciação Celular/imunologia , Regulação para Baixo/imunologia , Citometria de Fluxo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , MicroRNAs/genética , MicroRNAs/imunologia , Correpressor 2 de Receptor Nuclear/imunologia , Fenótipo , Proteínas Proto-Oncogênicas c-bcl-6/imunologia , RNA Mensageiro/biossíntese , RNA Mensageiro/química , RNA Mensageiro/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Proteínas com Domínio T/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Linfócitos T Auxiliares-Indutores/fisiologia , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/fisiologia , Transcrição GênicaRESUMO
Infectious hematopoietic necrosis (IHN), caused by IHN virus, is a highly contagious and lethal disease that seriously hampers the development of rainbow trout (Oncorhynchus mykiss) aquaculture. However, the immune response mechanism of rainbow trout underlying IHNV infection remains largely unknown. MicroRNAs act as post-transcriptional regulators of gene expression and perform a crucial role in fish immune response. Herein, the regulatory mechanism and function of miR-206 in rainbow trout resistance to IHNV were investigated by overexpression and silencing. The expression analysis showed that miR-206 and its potential target receptor-interacting serine/threonine-protein kinase 2 (RIP2) exhibited significant time-dependent changes in headkidney, spleen and rainbow trout primary liver cells infected with IHNV and their expression displayed a negative correlation. In vitro, the interaction between miR-206 and RIP2 was verified by luciferase reporter assay, and miR-206 silencing in rainbow trout primary liver cells markedly increased RIP2 and interferon (IFN) expression but significantly decreased IHNV copies, and opposite results were obtained after miR-206 overexpression or RIP2 knockdown. In vivo, overexpressed miR-206 with agomiR resulted in a decrease in the expression of RIP2 and IFN in liver, headkidney and spleen. This study revealed the key role of miR-206 in anti-IHNV, which provided potential for anti-viral drug screening in rainbow trout.
Assuntos
Doenças dos Peixes , Proteínas de Peixes , Vírus da Necrose Hematopoética Infecciosa , MicroRNAs , Oncorhynchus mykiss , Infecções por Rhabdoviridae , Animais , Oncorhynchus mykiss/imunologia , Oncorhynchus mykiss/genética , Doenças dos Peixes/imunologia , Doenças dos Peixes/virologia , Vírus da Necrose Hematopoética Infecciosa/fisiologia , Infecções por Rhabdoviridae/veterinária , Infecções por Rhabdoviridae/imunologia , MicroRNAs/genética , MicroRNAs/imunologia , MicroRNAs/metabolismo , Proteínas de Peixes/genética , Proteínas de Peixes/imunologia , Imunidade Inata/genéticaRESUMO
MicroRNAs are increasingly recognized for their pivotal role in the immune system, yet the specific regulatory functions of fish-derived microRNAs remain largely unexplored. In this research, we discovered a novel miRNA, Cse-miR-144, in the Chinese tongue sole (Cynoglossus semilaevis), characterized by a 73-base pair precursor and a 21-nucleotide mature sequence. Our findings revealed that the expression of Cse-miR-144 was notably inhibited by various Vibrio species. Utilizing bioinformatics and dual-luciferase assay techniques, we established that the pro-inflammatory cytokine gene CsMAPK6 is a direct target of Cse-miR-144. Subsequent in vitro and in vivo western blotting analyses confirmed that Cse-miR-144 can effectively reduce the protein levels of CsMAPK6 post-transcriptionally. Moreover, CsMAPK6 is known to be involved in the activation of the Nuclear Factor kappa-light-chain-enhancer of activated B cells (NF-kB). Additional investigations using qPCR and ELISA demonstrated that suppression of Cse-miR-144 leads to an upsurge in the liver mRNA levels of various immune genes (including MYD88, TRAF6, NF-κB, TRAF2, TRAF3, and TNF), alongside a marked increase in the production and secretion of pro-inflammatory cytokines (IL-1ß, IL-6, and IL-8) in the bloodstream of C. semilaevis. These findings collectively underscore the potential of Cse-miR-144 as a key inhibitor of CsMAPK and its crucial role in modulating the immune and inflammatory responses in teleost fish. Compared to the siRNA, miRNA is a better tool in controlling the expression of target gene with a lower cost.
Assuntos
Doenças dos Peixes , Proteínas de Peixes , Linguados , Regulação da Expressão Gênica , Imunidade Inata , MicroRNAs , Vibrioses , Vibrio , Animais , MicroRNAs/genética , MicroRNAs/imunologia , Linguados/imunologia , Linguados/genética , Doenças dos Peixes/imunologia , Proteínas de Peixes/genética , Proteínas de Peixes/imunologia , Vibrio/fisiologia , Imunidade Inata/genética , Regulação da Expressão Gênica/imunologia , Vibrioses/imunologia , Vibrioses/veterinária , Inflamação/imunologia , Inflamação/veterinária , Inflamação/genética , Citocinas/genética , Citocinas/imunologia , Citocinas/metabolismoRESUMO
Recent research has highlighted complex and close interaction between miRNAs, autophagy, and viral infection. In this study, we observed the autophagy status in CIK cells infected with GCRV at various time points. We found that GCRV consistently induced cellar autophagy from 0 h to 12 h post infection. Subsequently, we performed deep sequencing on CIK cells infected with GCRV at 0 h and 12 h respectively, identifying 38 DEMs and predicting 9581 target genes. With the functional enrichment analyses of GO and KEGG, we identified 35 autophagy-related target genes of these DEMs, among which akt3 was pinpointed as the most central hub gene using module assay of the PPI network. Then employing the miRanda and Targetscan programs for prediction, and verification through a double fluorescent enzyme system and qPCR method, we confirmed that miR-193 b-3p could target the 3'-UTR of grass carp akt3, reducing its gene expression. Ultimately, we illustrated that grass carp miR-193 b-3p could promote autophagy in CIK cells. Above results collectively indicated that miRNAs might play a critical role in autophagy of grass carp during GCRV infection and contributed significantly to antiviral immunity by targeting autophagy-related genes. This study may provide new insights into the intricate mechanisms involved in virus, autophagy, and miRNAs.