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1.
Hum Mol Genet ; 31(19): 3355-3366, 2022 09 29.
Artigo em Inglês | MEDLINE | ID: mdl-35640154

RESUMO

Recent studies identifying expression quantitative trait loci (eQTLs) in immune cells have uncovered important links between disease risk alleles and gene expression trends in monocytes, T cells and other cell types. However, these studies are generally done with young, healthy subjects, limiting the utility of their findings for age-related conditions such as Alzheimer's disease (AD). We have performed RNA sequencing on four T-cell subsets in genome-wide genotyped and well-characterized AD subjects and age- and sex-matched controls from the Religious Orders Study/Memory and Aging Project. We correlated gene expression data with AD neuropathological traits and with single-nucleotide polymorphisms to detect eQTLs. We identified several significant genes involved in T-cell senescence and cytotoxicity, consistent with T-cell RNA sequencing studies in aged/AD cohorts. We identified unexpected eQTLs previously associated with neuropsychiatric disease traits. Finally, we discovered that pathways related to axon guidance and synaptic function were enriched among trans-eQTLs in coding regions of the genome. Our data strengthen the potential link between T-cell senescence and age-related neurodegenerative disease. In addition, our eQTL data suggest that T-cell phenotypes may influence neuropsychiatric disorders and can be influenced by genes involved in neurodevelopmental processes.


Assuntos
Doença de Alzheimer , Doenças Neurodegenerativas , Humanos , Doença de Alzheimer/genética , Estudos de Associação Genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Polimorfismo de Nucleotídeo Único/genética , Linfócitos T
2.
Immunity ; 36(4): 623-34, 2012 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-22503540

RESUMO

Interleukin 9 (IL-9) is a pleiotropic cytokine that can regulate autoimmune responses by enhancing regulatory CD4(+)FoxP3(+) T regulatory (Treg) cell survival and T helper 17 (Th17) cell proliferation. Here, we analyzed the costimulatory requirements for the induction of Th9 cells, and demonstrated that Notch pathway cooperated with TGF-ß signaling to induce IL-9. Conditional ablation of Notch1 and Notch2 receptors inhibited the development of Th9 cells. Notch1 intracellular domain (NICD1) recruited Smad3, downstream of TGF-ß cytokine signaling, and together with recombining binding protein (RBP)-Jκ bound the Il9 promoter and induced its transactivation. In experimental autoimmune encephalomyelitis (EAE), Jagged2 ligation regulated clinical disease in an IL-9-dependent fashion. Signaling through Jagged2 expanded Treg cells and suppressed EAE when administered before antigen immunization, but worsened EAE when administered concurrently with immunization by favoring Th17 cell expansion. We propose that Notch and Smad3 cooperate to induce IL-9 and participate in regulating the immune response.


Assuntos
Encefalomielite Autoimune Experimental/imunologia , Interleucina-9/metabolismo , Receptor Notch1/metabolismo , Receptor Notch2/metabolismo , Proteína Smad3/metabolismo , Linfócitos T Auxiliares-Indutores/imunologia , Animais , Comunicação Celular , Diferenciação Celular , Encefalomielite Autoimune Experimental/metabolismo , Feminino , Proteína de Ligação a Sequências Sinal de Recombinação J de Imunoglobina/metabolismo , Interleucina-9/biossíntese , Proteína Jagged-2 , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Receptor Notch1/genética , Receptor Notch2/genética , Receptores de Interleucina-9/genética , Transdução de Sinais , Linfócitos T Auxiliares-Indutores/metabolismo , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Células Th17/imunologia , Células Th17/metabolismo , Fator de Crescimento Transformador beta
3.
Immunity ; 37(2): 249-63, 2012 Aug 24.
Artigo em Inglês | MEDLINE | ID: mdl-22884314

RESUMO

Inflammation-mediated neurodegeneration occurs in the acute and the chronic phases of multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE). Classically activated (M1) microglia are key players mediating this process. Here, we identified Galectin-1 (Gal1), an endogenous glycan-binding protein, as a pivotal regulator of M1 microglial activation that targets the activation of p38MAPK-, CREB-, and NF-κB-dependent signaling pathways and hierarchically suppresses downstream proinflammatory mediators, such as iNOS, TNF, and CCL2. Gal1 bound to core 2 O-glycans on CD45, favoring retention of this glycoprotein on the microglial cell surface and augmenting its phosphatase activity and inhibitory function. Gal1 was highly expressed in the acute phase of EAE, and its targeted deletion resulted in pronounced inflammation-induced neurodegeneration. Adoptive transfer of Gal1-secreting astrocytes or administration of recombinant Gal1 suppressed EAE through mechanisms involving microglial deactivation. Thus, Gal1-glycan interactions are essential in tempering microglial activation, brain inflammation, and neurodegeneration, with critical therapeutic implications for MS.


Assuntos
Encefalomielite Autoimune Experimental/imunologia , Galectina 1/imunologia , Antígenos Comuns de Leucócito/metabolismo , Microglia/imunologia , Animais , Astrócitos/metabolismo , Sistema Nervoso Central/imunologia , Sistema Nervoso Central/metabolismo , Sistema Nervoso Central/fisiopatologia , Quimiocina CCL2/metabolismo , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Encefalomielite Autoimune Experimental/metabolismo , Encefalomielite Autoimune Experimental/terapia , Feminino , Galectina 1/metabolismo , Galectina 1/uso terapêutico , Humanos , Interleucina-6/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microglia/citologia , Microglia/metabolismo , Esclerose Múltipla/imunologia , Esclerose Múltipla/metabolismo , Esclerose Múltipla/fisiopatologia , NF-kappa B/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Polissacarídeos/metabolismo , Ligação Proteica , Fator de Necrose Tumoral alfa/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
4.
Circulation ; 140(10): 846-863, 2019 09 09.
Artigo em Inglês | MEDLINE | ID: mdl-31266349

RESUMO

BACKGROUND: Transplantation is the treatment of choice for many patients with end-stage organ disease. Despite advances in immunosuppression, long-term outcomes remain suboptimal, hampered by drug toxicity and immune-mediated injury, the leading cause of late graft loss. The development of therapies that promote regulation while suppressing effector immunity is imperative to improve graft survival and minimize conventional immunosuppression. Notch signaling is a highly conserved pathway pivotal to T-cell differentiation and function, rendering it a target of interest in efforts to manipulate T cell-mediated immunity. METHODS: We investigated the pattern of Notch-1 expression in effector and regulatory T cells (Tregs) in both murine and human recipients of a solid-organ transplant. Using a selective human anti-Notch-1 antibody (aNotch-1), we examined the effect of Notch-1 receptor inhibition in full major histocompatibility complex-mismatch murine cardiac and lung transplant models, and in a humanized skin transplant model. On the basis of our findings, we further used a genetic approach to investigate the effect of selective Notch-1 inhibition in Tregs. RESULTS: We observed an increased proportion of Tregs expressing surface and intracellular (activated) Notch-1 in comparison with conventional T cells, both in mice with transplants and in the peripheral blood of patients with transplants. In the murine cardiac transplant model, peritransplant administration of aNotch-1 (days 0, 2, 4, 6, 8, and 10) significantly prolonged allograft survival in comparison with immunoglobulin G-treated controls. Similarly, aNotch-1 treatment improved both histological and functional outcomes in the murine lung transplant model. The use of aNotch-1 resulted in a reduced proportion of both splenic and intragraft conventional T cells, while increasing the proportion of Tregs. Furthermore, Tregs isolated from aNotch-1-treated mice showed enhanced suppressive function on a per-cell basis, confirmed with selective Notch-1 deletion in Tregs (Foxp3EGFPCreNotch1fl/fl). Notch-1 blockade inhibited the mammalian target of rapamycin pathway and increased the phosphorylation of STAT5 (signal transducer and activator of transcription 5) in murine Tregs. Notch-1low Tregs isolated from human peripheral blood exhibited more potent suppressive capacity than Notch-1high Tregs. Last, the combination of aNotch-1 with costimulation blockade induced long-term tolerance in a cardiac transplant model, and this tolerance was dependent on CTLA-4 (cytotoxic T-lymphocyte-associated antigen-4) signaling. CONCLUSIONS: Our data reveal a promising, clinically relevant approach for immune modulation in transplantation by selectively targeting Notch-1.


Assuntos
Rejeição de Enxerto/metabolismo , Receptor Notch1/antagonistas & inibidores , Subpopulações de Linfócitos T/imunologia , Linfócitos T Reguladores/imunologia , Animais , Anticorpos Bloqueadores/farmacologia , Células Cultivadas , Regulação da Expressão Gênica , Rejeição de Enxerto/imunologia , Rejeição de Enxerto/mortalidade , Humanos , Tolerância Imunológica , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Transplante de Órgãos , Receptor Notch1/genética , Receptor Notch1/metabolismo , Fator de Transcrição STAT5/metabolismo , Transdução de Sinais , Análise de Sobrevida
5.
Clin Immunol ; 217: 108498, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32531345

RESUMO

Interleukin (IL)-27 is a pleiotropic cytokine that initially was described as being pro-inflammatory and an inducer of T helper (Th)1 cells. In contrast, it has also been described as an anti-inflammatory cytokine in that it suppresses pro-inflammatory Th17 cells and induces anti-inflammatory IL-10 producing T regulatory (Tr)1 cells. While the majority of studies have been focused on the effects of IL-27 on T cells, human antigen-presenting cells express high levels of the IL-27 receptor ex vivo, in addition to being the major producer of IL-27. We report here that human monocytes are repressed by endogenous IL-27, in that the addition of an anti-IL-27 neutralizing antibody increases the production of pro-inflammatory cytokines ex vivo. We observed that neutralizing monocyte-derived IL-27 leads to increased IL-17A production by CD4+ T cells and a down-regulation of the IL-17 modulating ectonucleotidase CD39 on monocytes. The locus that contains the IL27 gene has been linked to susceptibility for type 1 diabetes (T1D). Interestingly, ex vivo monocytes from subjects with T1D produce more IL-27 suggesting this upregulation of IL-27 acts as a negative feedback loop to attempt to counterbalance the pro-inflammatory immune response in the disease state. In summary, we provide evidence that IL-27 is an endogenous regulator of human monocytes and has consequences on CD4+ T cell phenotype, particularly Th17 cells.


Assuntos
Interleucinas/metabolismo , Monócitos/imunologia , Células Th17/citologia , Células Th17/imunologia , Adulto , Diferenciação Celular/imunologia , Feminino , Humanos , Inflamação/imunologia , Interleucina-17/biossíntese , Interleucinas/antagonistas & inibidores , Interleucinas/genética , Masculino , Pessoa de Meia-Idade , Linfócitos T Reguladores/imunologia , Células Th1/imunologia , Adulto Jovem
6.
Nat Immunol ; 9(12): 1347-55, 2008 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-18997793

RESUMO

Transcription factor Foxp3 is critical for generating regulatory T cells (T(reg) cells). Transforming growth factor-beta (TGF-beta) induces Foxp3 and suppressive T(reg) cells from naive T cells, whereas interleukin 6 (IL-6) inhibits the generation of inducible T(reg) cells. Here we show that IL-4 blocked the generation of TGF-beta-induced Foxp3(+) T(reg) cells and instead induced a population of T helper cells that produced IL-9 and IL-10. The IL-9(+)IL-10(+) T cells demonstrated no regulatory properties despite producing abundant IL-10. Adoptive transfer of IL-9(+)IL-10(+) T cells into recombination-activating gene 1-deficient mice induced colitis and peripheral neuritis, the severity of which was aggravated if the IL-9(+)IL-10(+) T cells were transferred with CD45RB(hi) CD4(+) effector T cells. Thus IL-9(+)IL-10(+) T cells lack suppressive function and constitute a distinct population of helper-effector T cells that promote tissue inflammation.


Assuntos
Fatores de Transcrição Forkhead/imunologia , Interleucina-4/imunologia , Subpopulações de Linfócitos T/imunologia , Linfócitos T Reguladores/imunologia , Fator de Crescimento Transformador beta/imunologia , Transferência Adotiva , Animais , Diferenciação Celular/imunologia , Fatores de Transcrição Forkhead/metabolismo , Fator de Transcrição GATA3/imunologia , Fator de Transcrição GATA3/metabolismo , Interleucina-10/imunologia , Interleucina-10/metabolismo , Interleucina-4/metabolismo , Interleucina-9/imunologia , Interleucina-9/metabolismo , Ativação Linfocitária/imunologia , Camundongos , Camundongos Transgênicos , Fator de Transcrição STAT6/imunologia , Fator de Transcrição STAT6/metabolismo , Subpopulações de Linfócitos T/citologia , Linfócitos T Reguladores/citologia , Fator de Crescimento Transformador beta/metabolismo
7.
Brain Behav Immun ; 83: 180-191, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31604143

RESUMO

Microglia are resident immune cells of the central nervous system (CNS). The exact role of microglia in CNS disorders is not clear due to lack of tools to discriminate between microglia and infiltrating myeloid cells. Here, we present a novel reporter mouse model targeting a microglia-specific marker, TMEM119, for studying microglia in health and disease. By placing a reporter cassette (GSG-3xFlag-P2A-tdTomato) between the coding sequence of exon 2 and 3'UTR of the Tmem119 gene using CRISPR/Cas9 technology, we generated a Tmem119-tdTomato knock-in mouse strain. Gene expression assay showed no difference of endogenous Tmem119 in the CNS of Tmem119tdTomato/+ relative to wild-type mice. The cells expressing tdTomato were recognized by immunofluorescence staining using commercially available anti-TMEM119 antibodies. Additionally, immunofluorescence and flow cytometry techniques revealed that tdTomato+ cells are detected throughout the CNS, but not in peripheral tissues of Tmem119tdTomato/+ mice. Aging does not influence TMEM119 expression as tdTomato+ cells were detectable in the CNS of older mice (300 and 540 days old). Further immunofluorescence characterization shows that tdTomato+ cells colocalize with Iba1+ cells in the brain, but not with neurons, astrocytes or oligodendrocytes. Moreover, flow cytometry analysis of brain tissues of adult mice demonstrates that the majority of microglia CD45loCD11b+ cells (96.3%) are tdTomato-positive; and a minority of infiltrating CD45hiCD11b+ myeloid cells (5.3%) are also tdTomato-positive, which we further characterized and found that tdTomato expression is in part of choroid plexus macrophages but not in meningeal and perivascular macrophages. Functionally, using an acute injury model, we measured time-lapse activation of tdTomato-labeled microglia by transcranial two-photon microscopy in live Tmem119tdTomato/+ mice. Taken together, the Tmem119-tdTomato reporter mouse model is a valuable tool to specifically study the role of microglia in health and disease.


Assuntos
Sistema Nervoso Central/citologia , Sistema Nervoso Central/metabolismo , Genes Reporter , Proteínas Luminescentes/genética , Proteínas Luminescentes/metabolismo , Microglia/metabolismo , Modelos Animais , Animais , Feminino , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteína Vermelha Fluorescente
8.
Hum Mol Genet ; 25(2): 404-17, 2016 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-26604133

RESUMO

Notch signaling has recently emerged as an important regulator of immune responses in autoimmune diseases. The recombination signal-binding protein for immunoglobulin kappa J region (RBPJ) is a transcriptional repressor, but converts into a transcriptional activator upon activation of the canonical Notch pathway. Genome-wide association studies of rheumatoid arthritis (RA) identified a susceptibility locus, rs874040(CC), which implicated the RBPJ gene. Here, chromatin state mapping generated using the chromHMM algorithm reveals strong enhancer regions containing DNase I hypersensitive sites overlapping the rs874040 linkage disequilibrium block in human memory, but not in naïve CD4(+) T cells. The rs874040 overlapping this chromatin state was associated with increased RBPJ expression in stimulated memory CD4(+) T cells from healthy subjects homozygous for the risk allele (CC) compared with memory CD4(+) T cells bearing the protective allele (GG). Transcriptomic analysis of rs874040(CC) memory T cells showed a repression of canonical Notch target genes IL (interleukin)-9, IL-17 and interferon (IFN)γ in the basal state. Interestingly, activation of the Notch pathway using soluble Notch ligand, Jagged2-Fc, induced IL-9 and IL-17A while delta-like 4Fc, another Notch ligand, induced higher IFNγ expression in the rs874040(CC) memory CD4(+) T cells compared with their rs874040(GG) counterparts. In RA, RBPJ expression is elevated in memory T cells from RA patients compared with control subjects, and this was associated with induced inflammatory cytokines IL-9, IL-17A and IFNγ in response to Notch ligation in vitro. These findings demonstrate that the rs874040(CC) allele skews memory T cells toward a pro-inflammatory phenotype involving Notch signaling, thus increasing the susceptibility to develop RA.


Assuntos
Artrite Reumatoide/genética , Artrite Reumatoide/imunologia , Linfócitos T CD4-Positivos/imunologia , Predisposição Genética para Doença , Proteína de Ligação a Sequências Sinal de Recombinação J de Imunoglobina/genética , Polimorfismo de Nucleotídeo Único , Adulto , Artrite Reumatoide/metabolismo , Linfócitos T CD4-Positivos/metabolismo , Citocinas , Feminino , Expressão Gênica , Humanos , Proteína de Ligação a Sequências Sinal de Recombinação J de Imunoglobina/imunologia , Memória Imunológica , Masculino , Receptores Notch , Transdução de Sinais , Adulto Jovem
9.
Epilepsia ; 58 Suppl 3: 57-68, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28675562

RESUMO

Inflammatory mechanisms have been increasingly implicated in the origin of seizures and epilepsy. These mechanisms are involved in the genesis of encephalitides in which seizures are a common complaint. Experimental and clinical evidence suggests different inflammatory responses in the brains of patients with epilepsy depending on the etiology. In general, activation of both innate and adaptive immunity plays a role in refractory forms of epilepsy. Epilepsies in which seizures develop after infiltration of cells of the adaptive immune system in the central nervous system (CNS) include a broad range of epileptic disorders with different (known or unknown) etiologies. Infiltration of lymphocytes is observed in autoimmune epilepsies, especially the classical paraneoplastic encephalitides with antibodies against intracellular tumor antigens. The presence of lymphocytes in the CNS also has been found in focal cerebral dysplasia type 2 and in cortical tubers. Various autoantibodies have been shown to be associated with temporal lobe epilepsy (TLE) and hippocampal sclerosis of unknown etiology, which may be due to the presence of viral DNA. During the last decade, an increasing number of antineuronal autoantibodies directed against membranous epitopes have been discovered and are associated with various neurologic syndromes, including limbic encephalitis. A major challenge in epilepsy is to define biomarkers, which would allow the recognition of patient populations who might benefit from immune-modulatory therapies. Some peripheral inflammatory markers appear to be differentially expressed in patients with medically controlled and medically refractory and, as such, could be used for diagnostic, prognostic, or therapeutic purposes. Establishing an autoimmune basis in patients with drug-resistant epilepsy allows for efficacious and targeted immunotherapy. Although current immunotherapies can give great benefit to the correctly identified patient, there are limitations to their efficacy and they may have considerable side effects. Thus the identification of new immunomodulatory compounds remains of utmost importance.


Assuntos
Imunidade Adaptativa/imunologia , Epilepsia/imunologia , Imunidade Inata/imunologia , Autoanticorpos/metabolismo , Biomarcadores/metabolismo , Encéfalo/imunologia , Epilepsia Resistente a Medicamentos/imunologia , Epilepsia/terapia , Humanos , Imunomodulação , Imunoterapia , Linfócitos/imunologia , Neurônios/imunologia
10.
Ann Neurol ; 78(1): 115-27, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25914168

RESUMO

OBJECTIVE: A proportion of multiple sclerosis (MS) patients experience disease activity despite treatment. The early identification of the most effective drug is critical to impact long-term outcome and to move toward a personalized approach. The aim of the present study is to identify biomarkers for further clinical development and to yield insights into the pathophysiology of disease activity. METHODS: We performed a genome-wide association study in interferon-ß (IFNß)-treated MS patients followed by validation in 3 independent cohorts. The role of the validated variant was examined in several RNA data sets, and the function of the presumed target gene was explored using an RNA interference approach in primary T cells in vitro. RESULTS: We found an association between rs9828519(G) and nonresponse to IFNß (pdiscovery = 4.43 × 10(-8)) and confirmed it in a meta-analysis across 3 replication data sets (preplication = 7.78 × 10(-4)). Only 1 gene is found in the linkage disequilibrium block containing rs9828519: SLC9A9. Exploring the function of this gene, we see that SLC9A9 mRNA expression is diminished in MS subjects who are more likely to have relapses. Moreover, SLC9A9 knockdown in T cells in vitro leads an increase in expression of IFNγ, which is a proinflammatory molecule. INTERPRETATION: This study identifies and validates the role of rs9828519, an intronic variant in SLC9A9, in IFNß-treated subjects, demonstrating a successful pharmacogenetic screen in MS. Functional characterization suggests that SLC9A9, an Na(+) -H(+) exchanger found in endosomes, appears to influence the differentiation of T cells to a proinflammatory fate and may have a broader role in MS disease activity, outside of IFNß treatment.


Assuntos
Adjuvantes Imunológicos/uso terapêutico , Citocinas/imunologia , Interferon beta/uso terapêutico , Esclerose Múltipla Recidivante-Remitente/genética , Trocadores de Sódio-Hidrogênio/genética , Linfócitos T/imunologia , Adolescente , Adulto , Diferenciação Celular/genética , Células Cultivadas , Estudos de Coortes , Citocinas/genética , Citocinas/metabolismo , Feminino , Perfilação da Expressão Gênica , Técnicas de Silenciamento de Genes , Humanos , Técnicas In Vitro , Interferon beta-1a , Interferon beta-1b , Leucócitos Mononucleares/metabolismo , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Esclerose Múltipla Recidivante-Remitente/imunologia , RNA Interferente Pequeno , Linfócitos T/metabolismo , Adulto Jovem
11.
J Immunol ; 193(1): 198-207, 2014 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-24879792

RESUMO

The transcriptional repressor B cell lymphoma 6 (BCL6) is required for the development of Th follicular cells, and it has been shown to suppress Th2 cell differentiation. We demonstrate that BCL6 is a key regulator of Th9 cell development. BCL6 expression is transiently downregulated in polarized Th9 cells, and forced expression of BCL6 in Th9 cells impairs Th9 cell differentiation. In contrast, BCL6 knockdown upregulated IL-9 production in Th9 cells. The function of BCL6 in Th9 cells is under the control of IL-2/JAK3/STAT5 signaling pathway. Using chromatin immunoprecipitation, we show that, in Th9 cells, BCL6 and STAT5 bind to adjacent motifs in the Il9 promoter. Furthermore, we found that STAT5 binding was associated with the abundance of a permissive histone mark at the Il9 promoter, whereas under conditions in which BCL6 binding was predominant, a repressive histone mark was prevalent. The effects of STAT5 and BCL6 on IL-9 transcription were further demonstrated using an IL-9 luciferase reporter assay in which BCL6 repressed STAT5-mediated Il9 transactivation. In experimental autoimmune encephalomyelitis, forced expression of BCL6 in myelin oligodendrocyte glycoprotein35-55-specific Th9 cells resulted in decreased IL-9 production and induction of IFN-γ, causing an exacerbation of the clinical disease. Our findings demonstrate a novel role of BCL6 in the regulation of Th9 cell development and their encephalitogenicity.


Assuntos
Proteínas de Ligação a DNA/imunologia , Interleucina-9/imunologia , Transdução de Sinais/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Transcrição Gênica/imunologia , Ativação Transcricional/imunologia , Animais , Proteínas de Ligação a DNA/genética , Encefalomielite Autoimune Experimental/genética , Encefalomielite Autoimune Experimental/imunologia , Interferon gama/genética , Interferon gama/imunologia , Interleucina-2/genética , Interleucina-2/imunologia , Interleucina-9/genética , Janus Quinase 3/genética , Janus Quinase 3/imunologia , Camundongos , Camundongos Knockout , Proteínas Proto-Oncogênicas c-bcl-6 , Fator de Transcrição STAT5/genética , Fator de Transcrição STAT5/imunologia , Transdução de Sinais/genética , Linfócitos T Auxiliares-Indutores/patologia , Transcrição Gênica/genética , Ativação Transcricional/genética
12.
J Immunol ; 191(6): 3139-51, 2013 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-23960232

RESUMO

Although activated inflammatory monocytes (IMCs) and inflammatory dendritic cells (IDCs) are potent T cell suppressors, nonactivated IMCs and IDCs promote T cell activation and Th1/Th17 cell differentiation. In this study, we investigated how to reduce the proinflammatory properties of IMCs and IDCs and further convert them into immune regulatory dendritic cells (DCs). We found that IL-4 and retinoic acid (RA) cotreatment of GM-CSF-differentiated IDCs synergistically induced the expression of aldehyde dehydrogenase family 1, subfamily A2, a rate-limiting enzyme for RA synthesis in DCs. IL-4 plus RA-treated IDCs upregulated CD103 expression and markedly reduced the production of proinflammatory cytokines upon activation. IL-4 plus RA-treated IDCs strongly induced CD4⁺Foxp3⁺ regulatory T cell differentiation and suppressed Th1 and Th17 differentiation. Mechanistically, the transcription factors Stat6 and RA receptor ß play important roles in aldehyde dehydrogenase family 1, subfamily A2, induction. In addition, IL-4 and RA signaling pathways interact closely to enhance the regulatory function of treated DCs. Adoptive transfer of IL-4 plus RA-treated DCs significantly increased regulatory T cell frequency in vivo. Direct treatment with IL-4 and RA also markedly suppressed actively induced experimental autoimmune encephalomyelitis. Our data demonstrate the synergistic effect of IL-4 and RA in inducing a regulatory phenotype in IDCs, providing a potential treatment strategy for autoimmune diseases.


Assuntos
Aldeído Desidrogenase/biossíntese , Diferenciação Celular/imunologia , Células Dendríticas/imunologia , Interleucina-4/metabolismo , Tretinoína/metabolismo , Aldeído Desidrogenase/imunologia , Família Aldeído Desidrogenase 1 , Animais , Diferenciação Celular/efeitos dos fármacos , Imunoprecipitação da Cromatina , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/metabolismo , Feminino , Citometria de Fluxo , Immunoblotting , Interleucina-4/imunologia , Interleucina-4/farmacologia , Ativação Linfocitária/efeitos dos fármacos , Ativação Linfocitária/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fenótipo , Reação em Cadeia da Polimerase em Tempo Real , Retinal Desidrogenase , Tretinoína/imunologia , Tretinoína/farmacologia
13.
Eur J Immunol ; 43(6): 1449-58, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23526606

RESUMO

The Notch pathway is an important intercellular signaling pathway that plays a major role in controlling cell fate. Accumulating evidence indicates that Notch and its ligands present on antigen-presenting cells might be important mediators of T helper cell differentiation. In this study, we investigated the role of Jagged2 in murine cardiac transplantation by using a signaling Jagged2 mAb (Jag2) that activates recombinant signal-binding protein-Jκ. While administration of Jag2 mAb had little effect on graft survival in the fully allogeneic mismatched model BALB/c→B6, it hastened rejection in CD28-deficient recipients. Similarly, Jag2 precipitated rejection in the bm12→B6 model. In this MHC class II-mismatched model, allografts spontaneously survive for >56 days due to the emergence of Treg cells that inhibit the expansion of alloreactive T cells. The accelerated rejection was associated with upregulation of Th2 cytokines and proinflammatory cytokine IL-6, despite expansion of Treg cells. Incubation of Treg cells with recombinant IL-6 abrogated their inhibitory effects in vitro. Furthermore, neutralization of IL-6 in vivo protected Jag2-treated recipients from rejection and Jagged2 signaling was unable to further accelerate rejection in the absence of Treg cells. Our findings therefore suggest that Jagged2 signaling can affect graft acceptance by upregulation of IL-6 and consequent resistance to Treg-cell suppression.


Assuntos
Rejeição de Enxerto/imunologia , Transplante de Coração/imunologia , Interleucina-6/imunologia , Proteínas de Membrana/metabolismo , Linfócitos T Reguladores/efeitos dos fármacos , Células Th2/efeitos dos fármacos , Animais , Anticorpos Bloqueadores/administração & dosagem , Anticorpos Monoclonais/administração & dosagem , Antígenos CD28/genética , Células Cultivadas , Antígenos de Histocompatibilidade/imunologia , Proteína Jagged-2 , Proteínas de Membrana/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Mutantes , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Transdução de Sinais/imunologia , Linfócitos T Reguladores/imunologia , Células Th2/imunologia
14.
Front Immunol ; 15: 1337831, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38590520

RESUMO

Introduction: T cells, known for their ability to respond to an enormous variety of pathogens and other insults, are increasingly recognized as important mediators of pathology in neurodegeneration and other diseases. T cell gene expression phenotypes can be regulated by disease-associated genetic variants. Many complex diseases are better represented by polygenic risk than by individual variants. Methods: We first compute a polygenic risk score (PRS) for Alzheimer's disease (AD) using genomic sequencing data from a cohort of Alzheimer's disease (AD) patients and age-matched controls, and validate the AD PRS against clinical metrics in our cohort. We then calculate the PRS for several autoimmune disease, neurological disorder, and immune function traits, and correlate these PRSs with T cell gene expression data from our cohort. We compare PRS-associated genes across traits and four T cell subtypes. Results: Several genes and biological pathways associated with the PRS for these traits relate to key T cell functions. The PRS-associated gene signature generally correlates positively for traits within a particular category (autoimmune disease, neurological disease, immune function) with the exception of stroke. The trait-associated gene expression signature for autoimmune disease traits was polarized towards CD4+ T cell subtypes. Discussion: Our findings show that polygenic risk for complex disease and immune function traits can have varying effects on T cell gene expression trends. Several PRS-associated genes are potential candidates for therapeutic modulation in T cells, and could be tested in in vitro applications using cells from patients bearing high or low polygenic risk for AD or other conditions.


Assuntos
Doença de Alzheimer , Doenças Autoimunes , Humanos , Doença de Alzheimer/genética , Fenótipo , Risco , Transdução de Sinais/genética
15.
Res Sq ; 2024 Jan 24.
Artigo em Inglês | MEDLINE | ID: mdl-38343836

RESUMO

Murine studies have highlighted a crucial role for immune cells in the meninges in surveilling the central nervous system (CNS) and influencing neuroinflammation. However, how meningeal immunity is altered in human neurodegeneration and its effects on CNS inflammation is understudied. We performed the first single-cell analysis of the transcriptomes and T cell receptor (TCR) repertoire of 104,635 immune cells from 55 postmortem human brain and leptomeningeal tissues from donors with neurodegenerative diseases including amyotrophic lateral sclerosis, Alzheimer's disease, and Parkinson's disease. RNA and TCR sequencing from paired leptomeninges and brain allowed us to perform lineage tracing to identify the spatial trajectory of clonal T cells in the CNS and its borders. We propose that T cells activated in the brain emigrate to and establish residency in the leptomeninges where they likely contribute to impairments in lymphatic drainage and remotely to CNS inflammation by producing IFNγ and other cytokines. We identified regulatory networks local to the meninges including NK cell-mediated CD8 T cell killing which likely help to control meningeal inflammation. Collectively, these findings provide not only a foundation for future studies into brain border immune surveillance but also highlight important intercellular dynamics that could be leveraged to modulate neuroinflammation.

16.
J Clin Immunol ; 33 Suppl 1: S43-9, 2013 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-22941509

RESUMO

Tregitopes are regulatory T cell epitopes derived from immunoglobulin G (IgG) that stimulate CD25(+) FoxP3(+) T cells to expand. In conjunction with these Tregs, Tregitopes can prevent, treat, and even cure autoimmune disease in mouse models, suppress allo-specific responses in murine transplant models, inhibit CD8(+) T cell responses to recombinant adeno-associated virus (AAV) gene transfer vectors, and induce adaptive Tregs in DO11.10 mice. In this review of recent Tregitope studies, we summarize their effects in vitro and describe recent comparisons between intravenous IgG (IVIG) and Tregitopes in standard in vivo immune tolerance models. Further investigations of the mechanism of action of Tregitopes in the preclinical models described here will lead to clinical trials where Tregitopes may have the potential to alter the treatment of autoimmune disease, transplantation, and allergy, and to improve the efficiency of gene and protein replacement therapies.


Assuntos
Epitopos de Linfócito T/imunologia , Imunoglobulina G/imunologia , Linfócitos T Reguladores/imunologia , Animais , Doenças Autoimunes/imunologia , Doenças Autoimunes/terapia , Autoimunidade , Humanos , Tolerância Imunológica , Imunoglobulinas Intravenosas/imunologia , Imunoglobulinas Intravenosas/uso terapêutico , Pesquisa/tendências
17.
J Immunol ; 187(5): 2322-8, 2011 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-21813770

RESUMO

Notch signaling pathway plays an important role in T cell differentiation. Delta-like ligand (Dll)4, one of five known Notch ligands, has been implicated in regulating Th2 cell differentiation in animal models of human diseases. However, the role of Dll4 in Th1/Th17-mediated autoimmune diseases remains largely unknown. Using an anti-Dll4 blocking mAb, we show that neutralizing Dll4 during the induction phase of experimental autoimmune encephalomyelitis in C57BL/6 mice significantly increased the pool of CD4(+)Foxp3(+) regulatory T cells (Treg) in the periphery and in the CNS, and decreased the severity of clinical disease and CNS inflammation. Dll4 blockade promoted induction of myelin-specific Th2/Treg immune responses and impaired Th1/Th17 responses compared with IgG-treated mice. In vitro, we show that signaling with recombinant Dll4 inhibits the TGF-ß-induced Treg development, and inhibits Janus kinase 3-induced STAT5 phosphorylation, a transcription factor known to play a key role in Foxp3 expression and maintenance. Depletion of natural Treg using anti-CD25 Ab reversed the protective effects of anti-Dll4 Ab. These findings outline a novel role for Dll4-Notch signaling in regulating Treg development in EAE, making it an encouraging target for Treg-mediated immunotherapy in autoimmune diseases, such as multiple sclerosis.


Assuntos
Diferenciação Celular/imunologia , Encefalomielite Autoimune Experimental/imunologia , Peptídeos e Proteínas de Sinalização Intracelular/imunologia , Ativação Linfocitária/imunologia , Proteínas de Membrana/imunologia , Linfócitos T Reguladores/imunologia , Proteínas Adaptadoras de Transdução de Sinal , Animais , Western Blotting , Proteínas de Ligação ao Cálcio , Separação Celular , Encefalomielite Autoimune Experimental/patologia , Feminino , Citometria de Fluxo , Camundongos , Camundongos Endogâmicos C57BL , Transdução de Sinais/imunologia , Subpopulações de Linfócitos T/citologia , Subpopulações de Linfócitos T/imunologia , Linfócitos T Reguladores/citologia
18.
J Immunol ; 187(5): 2418-32, 2011 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-21824867

RESUMO

CD11b(+)Ly-6C(hi) cells, including inflammatory monocytes (IMCs) and inflammatory dendritic cells (IDCs), are important in infectious, autoimmune, and tumor models. However, their role in T cell regulation is controversial. In this article, we show that T cell regulation by IMCs and IDCs is determined by their activation state and is plastic during an immune response. Nonactivated IMCs and IDCs function as APCs, but activated IMCs and IDCs suppress T cells through NO production. Suppressive IMCs are induced by IFN-γ, GM-CSF, TNF-α, and CD154 derived from activated T cells during their interaction. In experimental autoimmune encephalomyelitis, CD11b(+)Ly-6C(hi) cells in the CNS are increasingly activated from disease onset to peak and switch their function from Ag presentation to T cell suppression. Furthermore, transfer of activated IMCs or IDCs enhances T cell apoptosis in the CNS and suppresses experimental autoimmune encephalomyelitis. These data highlight the interplay between innate and adaptive immunity: immunization leads to the expansion of Ly-6C(hi) myeloid cells initially promoting T cell function. As T cells become highly activated in the target tissue, they induce activation and NO production in Ly-6C(hi) myeloid cells, which in turn suppress T cells and lead to the contraction of local immune response.


Assuntos
Antígenos Ly/imunologia , Células Dendríticas/imunologia , Ativação Linfocitária/imunologia , Monócitos/imunologia , Linfócitos T/imunologia , Animais , Apresentação de Antígeno/imunologia , Diferenciação Celular/imunologia , Separação Celular , Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/patologia , Feminino , Citometria de Fluxo , Camundongos , Camundongos Transgênicos , Fenótipo , Linfócitos T/citologia
19.
J Immunol ; 187(9): 4629-38, 2011 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-21949024

RESUMO

The Notch signaling pathway has been recently shown to contribute to T cell differentiation in vitro. However, the in vivo function of Notch signaling in transplantation remains unknown. In this study, we investigated the importance of Delta1 in regulating the alloimmune response in vivo. Delta1 expression was upregulated on dendritic cells and monocytes/macrophages upon transplantation in a BALB/c into B6 vascularized cardiac transplant model. Whereas administration of anti-Delta1 mAb only slightly delayed survival of cardiac allografts in this fully MHC-mismatched model, it significantly prolonged graft survival in combination with single-dose CTLA4-Ig or in CD28 knockout recipients. The prolongation of allograft survival was associated with Th2 polarization and a decrease in Th1 and granzyme B-producing cytotoxic T cells. The survival benefit of Delta1 blockade was abrogated after IL-4 neutralization and in STAT6KO recipients, but was maintained in STAT4KO recipients, reinforcing the key role of Th2 cell development in its graft-prolonging effects. To our knowledge, these data demonstrate for the first time an important role of Delta1 in alloimmunity, identifying Delta1 ligand as a potential novel target for immunomodulation in transplantation.


Assuntos
Diferenciação Celular/imunologia , Regulação para Baixo/imunologia , Sobrevivência de Enxerto/imunologia , Transplante de Coração/imunologia , Peptídeos e Proteínas de Sinalização Intracelular/antagonistas & inibidores , Ativação Linfocitária/imunologia , Proteínas de Membrana/antagonistas & inibidores , Linfócitos T Citotóxicos/imunologia , Células Th1/imunologia , Animais , Diferenciação Celular/genética , Polaridade Celular/genética , Polaridade Celular/imunologia , Citotoxicidade Imunológica/genética , Regulação para Baixo/genética , Sobrevivência de Enxerto/genética , Transplante de Coração/patologia , Peptídeos e Proteínas de Sinalização Intracelular/uso terapêutico , Ativação Linfocitária/genética , Proteínas de Membrana/biossíntese , Proteínas de Membrana/uso terapêutico , Camundongos , Camundongos da Linhagem 129 , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Modelos Imunológicos , Linfócitos T Citotóxicos/citologia , Células Th1/citologia , Regulação para Cima/imunologia
20.
Clin Dev Immunol ; 2013: 570731, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-24324509

RESUMO

The Notch signaling pathway preservation across species hints to the indispensable role it plays during evolution. Over the last decade the science community has extensively studied the Notch signaling pathway, with Notch emerging as a key player in embryogenesis, tissue homeostasis, angiogenesis, and immunoregulation. Multiple sclerosis (MS) is an incurable yet treatable autoimmune chronic inflammatory disease of the central nervous system. The aim of this review is to provide a brief description of the Notch signaling pathway, and summarize the current literature implicating Notch in the pathogenesis of MS.


Assuntos
Esclerose Múltipla/imunologia , Esclerose Múltipla/metabolismo , Receptores Notch/metabolismo , Transdução de Sinais , Linfócitos T Auxiliares-Indutores/imunologia , Linfócitos T Auxiliares-Indutores/metabolismo , Animais , Proteínas de Ligação ao Cálcio/metabolismo , Diferenciação Celular/imunologia , Modelos Animais de Doenças , Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/metabolismo , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Proteínas de Membrana/metabolismo , Oligodendroglia/imunologia , Oligodendroglia/metabolismo , Proteínas Serrate-Jagged , Subpopulações de Linfócitos T/citologia , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Linfócitos T Auxiliares-Indutores/citologia
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