RESUMEN
T cell activation leads to dramatic shifts in cell metabolism to protect against pathogens and to orchestrate the action of other immune cells. Quiescent T cells require predominantly ATP-generating processes, whereas proliferating effector T cells require high metabolic flux through growth-promoting pathways. Further, functionally distinct T cell subsets require distinct energetic and biosynthetic pathways to support their specific functional needs. Pathways that control immune cell function and metabolism are intimately linked, and changes in cell metabolism at both the cell and system levels have been shown to enhance or suppress specific T cell functions. As a result of these findings, cell metabolism is now appreciated as a key regulator of T cell function specification and fate. This review discusses the role of cellular metabolism in T cell development, activation, differentiation, and function to highlight the clinical relevance and opportunities for therapeutic interventions that may be used to disrupt immune pathogenesis.
Asunto(s)
Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismo , Animales , Redes Reguladoras de Genes/genética , Redes Reguladoras de Genes/inmunología , Glucólisis/genética , Glucólisis/inmunología , Humanos , Neoplasias/genética , Neoplasias/inmunología , Neoplasias/metabolismo , Fosforilación/genética , Fosforilación/inmunología , Subgrupos de Linfocitos T/citologíaRESUMEN
Cytokine signaling via signal transducer and activator of transcription (STAT) proteins is crucial for optimal antiviral responses of natural killer (NK) cells. However, the pleiotropic effects of both cytokine and STAT signaling preclude the ability to precisely attribute molecular changes to specific cytokine-STAT modules. Here, we employed a multi-omics approach to deconstruct and rebuild the complex interaction of multiple cytokine signaling pathways in NK cells. Proinflammatory cytokines and homeostatic cytokines formed a cooperative axis to commonly regulate global gene expression and to further repress expression induced by type I interferon signaling. These cytokines mediated distinct modes of epigenetic regulation via STAT proteins, and collective signaling best recapitulated global antiviral responses. The most dynamically responsive genes were conserved across humans and mice, which included a cytokine-STAT-induced cross-regulatory program. Thus, an intricate crosstalk exists between cytokine signaling pathways, which governs NK cell responses.
Asunto(s)
Epigénesis Genética/inmunología , Infecciones por Herpesviridae/inmunología , Interleucinas/metabolismo , Células Asesinas Naturales/inmunología , Factores de Transcripción STAT/metabolismo , Animales , Separación Celular , Secuenciación de Inmunoprecipitación de Cromatina , Modelos Animales de Enfermedad , Femenino , Citometría de Flujo , Redes Reguladoras de Genes/inmunología , Infecciones por Herpesviridae/sangre , Infecciones por Herpesviridae/virología , Humanos , Inmunidad Innata/genética , Células Asesinas Naturales/metabolismo , Masculino , Ratones , Ratones Noqueados , Muromegalovirus/inmunología , Análisis de Componente Principal , RNA-Seq , Factores de Transcripción STAT/genética , Transducción de Señal/genética , Transducción de Señal/inmunologíaRESUMEN
Respiratory infections are common precursors to asthma exacerbations in children, but molecular immune responses that determine whether and how an infection causes an exacerbation are poorly understood. By using systems-scale network analysis, we identify repertoires of cellular transcriptional pathways that lead to and underlie distinct patterns of asthma exacerbation. Specifically, in both virus-associated and nonviral exacerbations, we demonstrate a set of core exacerbation modules, among which epithelial-associated SMAD3 signaling is upregulated and lymphocyte response pathways are downregulated early in exacerbation, followed by later upregulation of effector pathways including epidermal growth factor receptor signaling, extracellular matrix production, mucus hypersecretion, and eosinophil activation. We show an additional set of multiple inflammatory cell pathways involved in virus-associated exacerbations, in contrast to squamous cell pathways associated with nonviral exacerbations. Our work introduces an in vivo molecular platform to investigate, in a clinical setting, both the mechanisms of disease pathogenesis and therapeutic targets to modify exacerbations.
Asunto(s)
Asma/inmunología , Redes Reguladoras de Genes/inmunología , Transcriptoma/inmunología , Virosis/inmunología , Adolescente , Asma/genética , Asma/virología , Estudios de Casos y Controles , Niño , Resfriado Común/genética , Resfriado Común/inmunología , Resfriado Común/virología , Femenino , Humanos , Estudios Longitudinales , Masculino , Estudios Prospectivos , Transducción de Señal/genética , Transducción de Señal/inmunología , Virosis/genética , Virosis/virologíaRESUMEN
The transcription factor c-Maf induces the anti-inflammatory cytokine IL-10 in CD4+ T cells in vitro. However, the global effects of c-Maf on diverse immune responses in vivo are unknown. Here we found that c-Maf regulated IL-10 production in CD4+ T cells in disease models involving the TH1 subset of helper T cells (malaria), TH2 cells (allergy) and TH17 cells (autoimmunity) in vivo. Although mice with c-Maf deficiency targeted to T cells showed greater pathology in TH1 and TH2 responses, TH17 cell-mediated pathology was reduced in this context, with an accompanying decrease in TH17 cells and increase in Foxp3+ regulatory T cells. Bivariate genomic footprinting elucidated the c-Maf transcription-factor network, including enhanced activity of NFAT; this led to the identification and validation of c-Maf as a negative regulator of IL-2. The decreased expression of the gene encoding the transcription factor RORγt (Rorc) that resulted from c-Maf deficiency was dependent on IL-2, which explained the in vivo observations. Thus, c-Maf is a positive and negative regulator of the expression of cytokine-encoding genes, with context-specific effects that allow each immune response to occur in a controlled yet effective manner.
Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Regulación de la Expresión Génica/inmunología , Redes Reguladoras de Genes/inmunología , Interleucina-2/biosíntesis , Proteínas Proto-Oncogénicas c-maf/inmunología , Animales , Interleucina-2/inmunología , RatonesAsunto(s)
Regulación de la Expresión Génica/inmunología , Redes Reguladoras de Genes/inmunología , Genómica/historia , Técnicas Inmunológicas/historia , Ratones/inmunología , Animales , Genómica/métodos , Historia del Siglo XXI , Sistema Inmunológico , Técnicas Inmunológicas/métodos , Ratones/genéticaRESUMEN
Systemic Lupus Erythematosus (SLE) is characterized by B cells lacking IgD and CD27 (double negative; DN). We show that DN cell expansions reflected a subset of CXCR5- CD11c+ cells (DN2) representing pre-plasma cells (PC). DN2 cells predominated in African-American patients with active disease and nephritis, anti-Smith and anti-RNA autoantibodies. They expressed a T-bet transcriptional network; increased Toll-like receptor-7 (TLR7); lacked the negative TLR regulator TRAF5; and were hyper-responsive to TLR7. DN2 cells shared with activated naive cells (aNAV), phenotypic and functional features, and similar transcriptomes. Their PC differentiation and autoantibody production was driven by TLR7 in an interleukin-21 (IL-21)-mediated fashion. An in vivo developmental link between aNAV, DN2 cells, and PC was demonstrated by clonal sharing. This study defines a distinct differentiation fate of autoreactive naive B cells into PC precursors with hyper-responsiveness to innate stimuli, as well as establishes prominence of extra-follicular B cell activation in SLE, and identifies therapeutic targets.
Asunto(s)
Subgrupos de Linfocitos B/inmunología , Linfocitos B/inmunología , Lupus Eritematoso Sistémico/inmunología , Receptor Toll-Like 7/inmunología , Adulto , Anciano , Anciano de 80 o más Años , Subgrupos de Linfocitos B/metabolismo , Linfocitos B/metabolismo , Femenino , Redes Reguladoras de Genes/genética , Redes Reguladoras de Genes/inmunología , Humanos , Lupus Eritematoso Sistémico/genética , Lupus Eritematoso Sistémico/metabolismo , Masculino , Persona de Mediana Edad , Células Plasmáticas/inmunología , Células Plasmáticas/metabolismo , Receptor Toll-Like 7/genética , Receptor Toll-Like 7/metabolismo , Transcriptoma/genética , Transcriptoma/inmunología , Adulto JovenRESUMEN
FoxP3-expressing regulatory T (Treg) cells are essential for maintaining immune homeostasis. Activated Treg cells undergo further differentiation into an effector state that highly expresses genes critical for Treg cell function, although how this process is coordinated on a transcriptional level is poorly understood. Here, we demonstrate that mice lacking the transcription factor Myb in Treg cells succumbed to a multi-organ inflammatory disease. Myb was specifically expressed in, and required for the differentiation of, thymus-derived effector Treg cells. The combination of transcriptome and genomic footprint analyses revealed that Myb directly regulated a large proportion of the gene expression specific to effector Treg cells, identifying Myb as a critical component of the gene regulatory network controlling effector Treg cell differentiation and function.
Asunto(s)
Redes Reguladoras de Genes/inmunología , Homeostasis/inmunología , Activación de Linfocitos/inmunología , Proteínas Proto-Oncogénicas c-myb/inmunología , Linfocitos T Reguladores/inmunología , Animales , Diferenciación Celular/inmunología , Modelos Animales de Enfermedad , Citometría de Flujo , Perfilación de la Expresión Génica , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , TranscriptomaRESUMEN
Distinct molecular pathways govern the differentiation of CD8+ effector T cells into memory or exhausted T cells during acute and chronic viral infection, but these are not well studied in humans. Here, we employed an integrative systems immunology approach to identify transcriptional commonalities and differences between virus-specific CD8+ T cells from patients with persistent and spontaneously resolving hepatitis C virus (HCV) infection during the acute phase. We observed dysregulation of metabolic processes during early persistent infection that was linked to changes in expression of genes related to nucleosomal regulation of transcription, T cell differentiation, and the inflammatory response and correlated with subject age, sex, and the presence of HCV-specific CD4+ T cell populations. These early changes in HCV-specific CD8+ T cell transcription preceded the overt establishment of T cell exhaustion, making this signature a prime target in the search for the regulatory origins of T cell dysfunction in chronic viral infection.
Asunto(s)
Linfocitos T CD8-positivos/inmunología , Hepacivirus/inmunología , Hepatitis C Crónica/inmunología , Transcripción Genética/inmunología , Enfermedad Aguda , Inmunidad Adaptativa/genética , Inmunidad Adaptativa/inmunología , Adulto , Anciano , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/metabolismo , Linfocitos T CD4-Positivos/virología , Linfocitos T CD8-positivos/metabolismo , Linfocitos T CD8-positivos/virología , Análisis por Conglomerados , Femenino , Perfilación de la Expresión Génica/métodos , Redes Reguladoras de Genes/inmunología , Variación Genética/inmunología , Hepacivirus/fisiología , Hepatitis C Crónica/genética , Hepatitis C Crónica/virología , Humanos , Activación de Linfocitos/genética , Activación de Linfocitos/inmunología , Masculino , Persona de Mediana Edad , Análisis Multivariante , Factores de Tiempo , Adulto JovenRESUMEN
The mammalian immune system implements a remarkably effective set of mechanisms for fighting pathogens1. Its main components are haematopoietic immune cells, including myeloid cells that control innate immunity, and lymphoid cells that constitute adaptive immunity2. However, immune functions are not unique to haematopoietic cells, and many other cell types display basic mechanisms of pathogen defence3-5. To advance our understanding of immunology outside the haematopoietic system, here we systematically investigate the regulation of immune genes in the three major types of structural cells: epithelium, endothelium and fibroblasts. We characterize these cell types across twelve organs in mice, using cellular phenotyping, transcriptome sequencing, chromatin accessibility profiling and epigenome mapping. This comprehensive dataset revealed complex immune gene activity and regulation in structural cells. The observed patterns were highly organ-specific and seem to modulate the extensive interactions between structural cells and haematopoietic immune cells. Moreover, we identified an epigenetically encoded immune potential in structural cells under tissue homeostasis, which was triggered in response to systemic viral infection. This study highlights the prevalence and organ-specific complexity of immune gene activity in non-haematopoietic structural cells, and it provides a high-resolution, multi-omics atlas of the epigenetic and transcriptional networks that regulate structural cells in the mouse.
Asunto(s)
Endotelio/inmunología , Células Epiteliales/inmunología , Fibroblastos/inmunología , Regulación de la Expresión Génica/inmunología , Sistema Inmunológico/citología , Sistema Inmunológico/inmunología , Especificidad de Órganos/inmunología , Inmunidad Adaptativa , Animales , Cromatina/genética , Cromatina/metabolismo , Endotelio/citología , Epigénesis Genética/inmunología , Epigenoma/genética , Células Epiteliales/citología , Femenino , Fibroblastos/citología , Regulación de la Expresión Génica/genética , Redes Reguladoras de Genes/genética , Redes Reguladoras de Genes/inmunología , Células Madre Hematopoyéticas/citología , Células Madre Hematopoyéticas/inmunología , Sistema Inmunológico/virología , Inmunidad Innata , Coriomeningitis Linfocítica/inmunología , Coriomeningitis Linfocítica/virología , Virus de la Coriomeningitis Linfocítica/inmunología , Masculino , Ratones , Especificidad de Órganos/genética , Transcripción Genética/inmunología , Transcriptoma/genéticaRESUMEN
The differentiation of hematopoietic stem cells into cells of the immune system has been studied extensively in mammals, but the transcriptional circuitry that controls it is still only partially understood. Here, the Immunological Genome Project gene-expression profiles across mouse immune lineages allowed us to systematically analyze these circuits. To analyze this data set we developed Ontogenet, an algorithm for reconstructing lineage-specific regulation from gene-expression profiles across lineages. Using Ontogenet, we found differentiation stage-specific regulators of mouse hematopoiesis and identified many known hematopoietic regulators and 175 previously unknown candidate regulators, as well as their target genes and the cell types in which they act. Among the previously unknown regulators, we emphasize the role of ETV5 in the differentiation of γδ T cells. As the transcriptional programs of human and mouse cells are highly conserved, it is likely that many lessons learned from the mouse model apply to humans.
Asunto(s)
Algoritmos , Regulación de la Expresión Génica/inmunología , Sistema Inmunológico/metabolismo , Transcripción Genética/inmunología , Animales , Diferenciación Celular/genética , Diferenciación Celular/inmunología , Linaje de la Célula/genética , Linaje de la Célula/inmunología , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/inmunología , Perfilación de la Expresión Génica , Redes Reguladoras de Genes/inmunología , Humanos , Sistema Inmunológico/citología , Ratones , Análisis de Secuencia por Matrices de Oligonucleótidos , Receptores de Antígenos de Linfocitos T gamma-delta/inmunología , Receptores de Antígenos de Linfocitos T gamma-delta/metabolismo , Proteínas Represoras/genética , Proteínas Represoras/inmunología , Linfocitos T/inmunología , Linfocitos T/metabolismo , Transactivadores/genética , Transactivadores/inmunología , Factores de Transcripción/genética , Factores de Transcripción/inmunología , Transcriptoma/genética , Transcriptoma/inmunologíaRESUMEN
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.
Asunto(s)
Linfocitos T CD8-positivos/inmunología , Interferones/inmunología , MicroARNs/inmunología , Transducción de Señal/inmunología , Animales , Linfocitos T CD8-positivos/metabolismo , Proliferación Celular/efectos de los fármacos , Citometría de Flujo , Perfilación de la Expresión Génica , Redes Reguladoras de Genes/genética , Redes Reguladoras de Genes/inmunología , Immunoblotting , Memoria Inmunológica/genética , Memoria Inmunológica/inmunología , Factor 7 Regulador del Interferón/genética , Factor 7 Regulador del Interferón/inmunología , Factor 7 Regulador del Interferón/metabolismo , Interferones/metabolismo , Interferones/farmacología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , MicroARNs/genética , MicroARNs/metabolismo , Análisis de Secuencia por Matrices de Oligonucleótidos , Orthomyxoviridae/inmunología , Infecciones por Orthomyxoviridae/genética , Infecciones por Orthomyxoviridae/inmunología , Infecciones por Orthomyxoviridae/virología , Interferencia de ARN , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Factor de Transcripción STAT1/genética , Factor de Transcripción STAT1/inmunología , Factor de Transcripción STAT1/metabolismo , Transducción de Señal/genética , Proteína 1 Supresora de la Señalización de Citocinas , Proteínas Supresoras de la Señalización de Citocinas/genética , Proteínas Supresoras de la Señalización de Citocinas/inmunología , Proteínas Supresoras de la Señalización de Citocinas/metabolismoRESUMEN
B cell development is often depicted as a linear process initiating in the fetus and continuing postnatally. Using a PU.1 hypomorphic mouse model, we found that B-1 and B-2 lymphopoiesis occurred in distinct fetal and adult waves differentially dependent on the Sfpi1 14 kB upstream regulatory element. The initial wave of fetal B-1 development was absent in PU.1 hypomorphic mice, while subsequent fetal and adult waves emerged. In contrast, B-2 lymphopoiesis occurred in distinct fetal and adult waves. Whole-transcriptome profiling of fetal and adult B cell progenitors supported the existence of three waves of B-1 and two waves of B-2 development and revealed that the network of transcription factors governing B lineage specification and commitment was highly divergent between B-1 and B-2 progenitors. These findings support the view that the B-1 and B-2 lineages are distinct and provide a genetic basis for layering of immune system development.
Asunto(s)
Subgrupos de Linfocitos B/inmunología , Redes Reguladoras de Genes/inmunología , Linfopoyesis/inmunología , Animales , Linaje de la Célula/inmunología , Feto/inmunología , Perfilación de la Expresión Génica/métodos , Ratones , Células Precursoras de Linfocitos B/inmunología , Factores de Transcripción/inmunologíaRESUMEN
Macrophages undergo metabolic rewiring during polarization but details of this process are unclear. In this issue of Immunity, Jha et al. (2015) report a systems approach for unbiased analysis of cellular metabolism that reveals key metabolites and metabolic pathways required for distinct macrophage polarization states.
Asunto(s)
Redes Reguladoras de Genes/inmunología , Inmunidad Innata , Macrófagos/metabolismo , Mitocondrias/metabolismo , Transcripción Genética/inmunología , AnimalesRESUMEN
Many functionally important interactions between genes and proteins involved in immunological diseases and processes are unknown. The exponential growth in public high-throughput data offers an opportunity to expand this knowledge. To unlock human-immunology-relevant insight contained in the global biomedical research effort, including all public high-throughput datasets, we performed immunological-pathway-focused Bayesian integration of a comprehensive, heterogeneous compendium comprising 38,088 genome-scale experiments. The distillation of this knowledge into immunological networks of functional relationships between molecular entities (ImmuNet), and tools to mine this resource, are accessible to the public at http://immunet.princeton.edu. The predictive capacity of ImmuNet, established by rigorous statistical validation, is easily accessed by experimentalists to generate data-driven hypotheses. We demonstrate the power of this approach through the identification of unique host-virus interaction responses, and we show how ImmuNet complements genetic studies by predicting disease-associated genes. ImmuNet should be widely beneficial for investigating the mechanisms of the human immune system and immunological diseases.
Asunto(s)
Biología Computacional/métodos , Enfermedades del Sistema Inmune/inmunología , Sistema Inmunológico/inmunología , Mapeo de Interacción de Proteínas/métodos , Transducción de Señal/inmunología , Algoritmos , Teorema de Bayes , Redes Reguladoras de Genes/genética , Redes Reguladoras de Genes/inmunología , Interacciones Huésped-Patógeno/inmunología , Humanos , Sistema Inmunológico/metabolismo , Enfermedades del Sistema Inmune/genética , Internet , Mapas de Interacción de Proteínas/genética , Mapas de Interacción de Proteínas/inmunología , Reproducibilidad de los Resultados , Transducción de Señal/genética , Máquina de Vectores de Soporte , Transcriptoma/genética , Transcriptoma/inmunología , Virosis/genética , Virosis/inmunología , Virosis/virologíaRESUMEN
Macrophage polarization involves a coordinated metabolic and transcriptional rewiring that is only partially understood. By using an integrated high-throughput transcriptional-metabolic profiling and analysis pipeline, we characterized systemic changes during murine macrophage M1 and M2 polarization. M2 polarization was found to activate glutamine catabolism and UDP-GlcNAc-associated modules. Correspondingly, glutamine deprivation or inhibition of N-glycosylation decreased M2 polarization and production of chemokine CCL22. In M1 macrophages, we identified a metabolic break at Idh, the enzyme that converts isocitrate to alpha-ketoglutarate, providing mechanistic explanation for TCA cycle fragmentation. (13)C-tracer studies suggested the presence of an active variant of the aspartate-arginosuccinate shunt that compensated for this break. Consistently, inhibition of aspartate-aminotransferase, a key enzyme of the shunt, inhibited nitric oxide and interleukin-6 production in M1 macrophages, while promoting mitochondrial respiration. This systems approach provides a highly integrated picture of the physiological modules supporting macrophage polarization, identifying potential pharmacologic control points for both macrophage phenotypes.
Asunto(s)
Redes Reguladoras de Genes/inmunología , Inmunidad Innata , Macrófagos/metabolismo , Mitocondrias/metabolismo , Transcripción Genética/inmunología , Animales , Ácido Argininosuccínico/inmunología , Ácido Argininosuccínico/metabolismo , Aspartato Aminotransferasa Mitocondrial/genética , Aspartato Aminotransferasa Mitocondrial/inmunología , Ácido Aspártico/inmunología , Ácido Aspártico/metabolismo , Quimiocina CCL22/genética , Quimiocina CCL22/inmunología , Ciclo del Ácido Cítrico , Regulación de la Expresión Génica , Glutamina/deficiencia , Glicosilación , Interleucina-6/genética , Interleucina-6/inmunología , Isocitrato Deshidrogenasa/genética , Isocitrato Deshidrogenasa/inmunología , Macrófagos/clasificación , Macrófagos/citología , Macrófagos/inmunología , Redes y Vías Metabólicas/genética , Redes y Vías Metabólicas/inmunología , Ratones , Mitocondrias/genética , Mitocondrias/inmunología , Óxido Nítrico/inmunología , Óxido Nítrico/metabolismo , Transducción de Señal , Uridina Difosfato N-Acetilglucosamina/inmunología , Uridina Difosfato N-Acetilglucosamina/metabolismoRESUMEN
Migratory non-lymphoid tissue dendritic cells (NLT-DCs) transport antigens to lymph nodes (LNs) and are required for protective immune responses in the context of inflammation and to promote tolerance to self-antigens in steady-state. However, the molecular mechanisms that elicit steady-state NLT-DC maturation and migration are unknown. By comparing the transcriptome of NLT-DCs in the skin with their migratory counterparts in draining LNs, we have identified a novel NF-κB-regulated gene network specific to migratory DCs. We show that targeted deletion of IKKß in DCs, a major activator of NF-κB, prevents NLT-DC accumulation in LNs and compromises regulatory T cell conversion in vivo. This was associated with impaired tolerance and autoimmunity. NF-κB is generally considered the prototypical pro-inflammatory transcription factor, but this study describes a role for NF-κB signaling in DCs for immune homeostasis and tolerance that could have implications in autoimmune diseases and immunity.
Asunto(s)
Células Dendríticas/inmunología , Redes Reguladoras de Genes/inmunología , Homeostasis/inmunología , Tolerancia Inmunológica , FN-kappa B/inmunología , Transducción de Señal/inmunología , Animales , Autoantígenos/genética , Autoantígenos/inmunología , Autoinmunidad , Movimiento Celular , Células Dendríticas/citología , Perfilación de la Expresión Génica , Regulación de la Expresión Génica , Quinasa I-kappa B/deficiencia , Quinasa I-kappa B/genética , Quinasa I-kappa B/inmunología , Ganglios Linfáticos/citología , Ganglios Linfáticos/inmunología , Ratones , Ratones Noqueados , Análisis por Micromatrices , FN-kappa B/genética , Piel/citología , Piel/inmunología , Bazo/citología , Bazo/inmunología , Linfocitos T Reguladores/citología , Linfocitos T Reguladores/inmunologíaRESUMEN
While root diseases are among the most devastating stresses in global crop production, our understanding of root immunity is still limited relative to our knowledge of immune responses in leaves. Considering that root performance is based on the concerted functions of its different cell types, we undertook a cell type-specific transcriptome analysis to identify gene networks activated in epidermis, cortex, and pericycle cells of Arabidopsis (Arabidopsis thaliana) roots challenged with two immunity elicitors, the bacterial flagellin-derived flg22 and the endogenous Pep1 peptide. Our analyses revealed distinct immunity gene networks in each cell type. To further substantiate our understanding of regulatory patterns underlying these cell type-specific immunity networks, we developed a tool to analyze paired transcription factor binding motifs in the promoters of cell type-specific genes. Our study points toward a connection between cell identity and cell type-specific immunity networks that might guide cell types in launching immune response according to the functional capabilities of each cell type.
Asunto(s)
Arabidopsis/citología , Arabidopsis/inmunología , Redes Reguladoras de Genes/inmunología , Raíces de Plantas/inmunología , Arabidopsis/fisiología , Proteínas de Arabidopsis , Basidiomycota , Sitios de Unión , Regulación de la Expresión Génica de las Plantas , Células Vegetales/inmunología , Inmunidad de la Planta/genética , Inmunidad de la Planta/fisiología , Raíces de Plantas/citología , Raíces de Plantas/microbiología , Plantas Modificadas Genéticamente , Regiones Promotoras Genéticas , Transducción de Señal , TransactivadoresRESUMEN
Recent human genetic studies suggest that cells of the innate immune system have a primary role in the pathogenesis of neurodegenerative diseases. However, the results from these studies often do not elucidate how the genetic variants affect the biology of these cells to modulate disease risk. Here, we applied a tensor decomposition method to uncover disease associated gene networks linked to distal genetic variation in stimulated human monocyte and macrophage gene expression profiles. We report robust evidence that some disease associated genetic variants affect the expression of multiple genes in trans. These include a Parkinson's disease locus influencing the expression of genes mediated by a protease that controls lysosomal function, and Alzheimer's disease loci influencing the expression of genes involved in type 1 interferon signaling, myeloid phagocytosis, and complement cascade pathways. Overall, we uncover gene networks in induced innate immune cells linked to disease associated genetic variants, which may help elucidate the underlying biology of disease.
Asunto(s)
Enfermedad de Alzheimer/genética , Predisposición Genética a la Enfermedad , Modelos Genéticos , Enfermedad de Parkinson/genética , Sitios de Carácter Cuantitativo/inmunología , Enfermedad de Alzheimer/inmunología , Línea Celular , Mapeo Cromosómico , Conjuntos de Datos como Asunto , Perfilación de la Expresión Génica , Redes Reguladoras de Genes/inmunología , Variación Genética/inmunología , Estudio de Asociación del Genoma Completo , Humanos , Inmunidad Innata/genética , Interferón gamma/inmunología , Lipopolisacáridos/inmunología , Macrófagos/inmunología , Macrófagos/metabolismo , Monocitos/inmunología , Monocitos/metabolismo , Análisis de Secuencia por Matrices de Oligonucleótidos , Enfermedad de Parkinson/inmunologíaRESUMEN
Diverse gene regulatory mechanisms impact on immune homeostasis, and a new model now emerges as fundamental in light of recent genome-wide studies. In this picture, transcriptional networks drive functional changes during immune activation, whereas autoregulatory feedback loops of post-transcriptional programs ensure the original cell lineage identity and subsequent immune resolution.