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1.
Immunity ; 50(2): 362-377.e6, 2019 02 19.
Artigo em Inglês | MEDLINE | ID: mdl-30709738

RESUMO

Regulatory T (Treg) cells maintain immune tolerance through the master transcription factor forkhead box P3 (FOXP3), which is crucial for Treg cell function and homeostasis. We identified an IPEX (immune dysregulation polyendocrinopathy enteropathy X-linked) syndrome patient with a FOXP3 mutation in the domain swap interface of the protein. Recapitulation of this Foxp3 variant in mice led to the development of an autoimmune syndrome consistent with an unrestrained T helper type 2 (Th2) immune response. Genomic analysis of Treg cells by RNA-sequencing, Foxp3 chromatin immunoprecipitation followed by high-throughput DNA sequencing (ChIP-sequencing), and H3K27ac-HiChIP revealed a specific de-repression of the Th2 transcriptional program leading to the generation of Th2-like Treg cells that were unable to suppress extrinsic Th2 cells. Th2-like Treg cells showed increased intra-chromosomal interactions in the Th2 locus, leading to type 2 cytokine production. These findings identify a direct role for Foxp3 in suppressing Th2-like Treg cells and implicate additional pathways that could be targeted to restrain Th2 trans-differentiated Treg cells.


Assuntos
Fatores de Transcrição Forkhead/imunologia , Mutação , Linfócitos T Reguladores/imunologia , Células Th2/imunologia , Animais , Diferenciação Celular/genética , Diferenciação Celular/imunologia , Criança , Citocinas/genética , Citocinas/imunologia , Citocinas/metabolismo , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/metabolismo , Regulação da Expressão Gênica , Doenças Genéticas Ligadas ao Cromossomo X/genética , Doenças Genéticas Ligadas ao Cromossomo X/imunologia , Doenças Genéticas Ligadas ao Cromossomo X/metabolismo , Humanos , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Poliendocrinopatias Autoimunes/genética , Poliendocrinopatias Autoimunes/imunologia , Poliendocrinopatias Autoimunes/metabolismo , Linfócitos T Reguladores/metabolismo , Células Th2/metabolismo
2.
Immunity ; 42(2): 227-238, 2015 Feb 17.
Artigo em Inglês | MEDLINE | ID: mdl-25680271

RESUMO

Regulatory T cells (Treg cells) are required for immune homeostasis. Chromatin remodeling is essential for establishing diverse cellular identities, but how the epigenetic program in Treg cells is maintained throughout the dynamic activation process remains unclear. Here we have shown that CD28 co-stimulation, an extracellular cue intrinsically required for Treg cell maintenance, induced the chromatin-modifying enzyme, Ezh2. Treg-specific ablation of Ezh2 resulted in spontaneous autoimmunity with reduced Foxp3(+) cells in non-lymphoid tissues and impaired resolution of experimental autoimmune encephalomyelitis. Utilizing a model designed to selectively deplete wild-type Treg cells in adult mice co-populated with Ezh2-deficient Treg cells, Ezh2-deficient cells were destabilized and failed to prevent autoimmunity. After activation, the transcriptome of Ezh2-deficient Treg cells was disrupted, with altered expression of Treg cell lineage genes in a pattern similar to Foxp3-deficient Treg cells. These studies reveal a critical role for Ezh2 in the maintenance of Treg cell identity during cellular activation.


Assuntos
Antígenos CD28/imunologia , Ativação Linfocitária/imunologia , Complexo Repressor Polycomb 2/imunologia , Linfócitos T Reguladores/imunologia , Animais , Autoimunidade/genética , Autoimunidade/imunologia , Linfócitos T CD8-Positivos/imunologia , Montagem e Desmontagem da Cromatina , Encefalomielite Autoimune Experimental/imunologia , Proteína Potenciadora do Homólogo 2 de Zeste , Feminino , Fatores de Transcrição Forkhead/biossíntese , Fatores de Transcrição Forkhead/genética , Regulação da Expressão Gênica , Fator de Crescimento Semelhante a EGF de Ligação à Heparina/genética , Tolerância Imunológica/genética , Tolerância Imunológica/imunologia , Depleção Linfocítica , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Complexo Repressor Polycomb 2/genética , Regiões Promotoras Genéticas/genética , Linfócitos T Reguladores/citologia
3.
Immunity ; 39(5): 949-62, 2013 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-24238343

RESUMO

Stable Foxp3 expression is crucial for regulatory T (Treg) cell function. We observed that antigen-driven activation and inflammation in the CNS promoted Foxp3 instability selectively in the autoreactive Treg cells that expressed high amounts of Foxp3 before experimental autoimmune encephalitis induction. Treg cells with a demethylated Treg-cell-specific demethylated region in the Foxp3 locus downregulated Foxp3 transcription in the inflamed CNS during the induction phase of the response. Stable Foxp3 expression returned at the population level with the resolution of inflammation or was rescued by IL-2-anti-IL-2 complex treatment during the antigen priming phase. Thus, a subset of fully committed self-antigen-specific Treg cells lost Foxp3 expression during an inflammatory autoimmune response and might be involved in inadequate control of autoimmunity. These results have important implications for Treg cell therapies and give insights into the dynamics of the Treg cell network during autoreactive CD4(+) T cell effector responses in vivo.


Assuntos
Autoantígenos/imunologia , Encefalomielite Autoimune Experimental/imunologia , Fatores de Transcrição Forkhead/fisiologia , Regulação da Expressão Gênica/imunologia , Linfócitos T Reguladores/imunologia , Animais , Linfócitos T CD4-Positivos/imunologia , Linhagem da Célula , Sistema Nervoso Central/imunologia , Metilação de DNA , Regulação para Baixo/imunologia , Fatores de Transcrição Forkhead/biossíntese , Fatores de Transcrição Forkhead/genética , Genes Reporter , Linfonodos/imunologia , Ativação Linfocitária , Camundongos , Camundongos Endogâmicos C57BL , Glicoproteína Mielina-Oligodendrócito/imunologia , Fragmentos de Peptídeos/imunologia , Receptores de Interleucina-2/fisiologia , Proteínas Recombinantes de Fusão/imunologia , Sequências Reguladoras de Ácido Nucleico , Organismos Livres de Patógenos Específicos
4.
Nat Immunol ; 10(9): 1000-7, 2009 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-19633673

RESUMO

Regulatory T cells (T(reg) cells) are central to the maintenance of immune homeostasis. However, little is known about the stability of T(reg) cells in vivo. In this study, we demonstrate that a substantial percentage of cells had transient or unstable expression of the transcription factor Foxp3. These 'exFoxp3' T cells had an activated-memory T cell phenotype and produced inflammatory cytokines. Moreover, exFoxp3 cell numbers were higher in inflamed tissues in autoimmune conditions. Adoptive transfer of autoreactive exFoxp3 cells led to the rapid onset of diabetes. Finally, analysis of the T cell receptor repertoire suggested that exFoxp3 cells developed from both natural and adaptive T(reg) cells. Thus, the generation of potentially autoreactive effector T cells as a consequence of Foxp3 instability has important implications for understanding autoimmune disease pathogenesis.


Assuntos
Fatores de Transcrição Forkhead/fisiologia , Memória Imunológica , Linfócitos T Reguladores/fisiologia , Transferência Adotiva , Sequência de Aminoácidos , Animais , Doenças Autoimunes/etiologia , Regiões Determinantes de Complementaridade/química , Ilhas de CpG , Metilação de DNA , Células-Tronco Hematopoéticas/fisiologia , Imunofenotipagem , Interferon gama/biossíntese , Interleucina-17/biossíntese , Interleucina-2/farmacologia , Proteínas Luminescentes/metabolismo , Camundongos , Camundongos Endogâmicos NOD , Dados de Sequência Molecular , Receptores de Antígenos de Linfócitos T/fisiologia
5.
J Immunol ; 191(4): 1594-605, 2013 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-23858035

RESUMO

microRNAs (miRNA) are essential for regulatory T cell (Treg) function but little is known about the functional relevance of individual miRNA loci. We identified the miR-17-92 cluster as CD28 costimulation dependent, suggesting that it may be key for Treg development and function. Although overall immune homeostasis was maintained in mice with miR-17-92-deficient Tregs, expression of the miR-17-92 miRNA cluster was critical for Treg accumulation and function during an acute organ-specific autoimmune disease in vivo. Treg-specific loss of miR-17-92 expression resulted in exacerbated experimental autoimmune encephalitis and failure to establish clinical remission. Using peptide-MHC tetramers, we demonstrate that the miR-17-92 cluster was specifically required for the accumulation of activated Ag-specific Treg and for differentiation into IL-10-producing effector Treg.


Assuntos
Encefalomielite Autoimune Experimental/imunologia , MicroRNAs/imunologia , Subpopulações de Linfócitos T/imunologia , Linfócitos T Reguladores/imunologia , Adulto , Animais , Apresentação de Antígeno , Proteínas Reguladoras de Apoptose/genética , Proteína 11 Semelhante a Bcl-2 , Antígenos CD28/imunologia , Células Cultivadas , Receptores Coestimuladores e Inibidores de Linfócitos T/imunologia , Epitopos de Linfócito T/imunologia , Deleção de Genes , Heterozigoto , Antígenos de Histocompatibilidade Classe II/imunologia , Homeostase , Humanos , Interleucina-10/biossíntese , Ativação Linfocitária , Masculino , Proteínas de Membrana/genética , Camundongos , Camundongos Knockout , MicroRNAs/genética , Glicoproteína Mielina-Oligodendrócito/imunologia , PTEN Fosfo-Hidrolase/deficiência , Fragmentos de Peptídeos/imunologia , Proteínas Proto-Oncogênicas/genética , RNA Longo não Codificante , Adulto Jovem
6.
J Autoimmun ; 45: 58-67, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23850635

RESUMO

The non-obese diabetic (NOD) mouse is susceptible to the development of autoimmune diabetes but also multiple other autoimmune diseases. Over twenty susceptibility loci linked to diabetes have been identified in NOD mice and progress has been made in the definition of candidate genes at many of these loci (termed Idd for insulin-dependent diabetes). The susceptibility to multiple autoimmune diseases in the NOD background is a unique opportunity to examine susceptibility genes that confer a general propensity for autoimmunity versus susceptibility genes that control individual autoimmune diseases. We previously showed that NOD mice deficient for the costimulatory molecule B7-2 (NOD-B7-2KO mice) were protected from diabetes but spontaneously developed an autoimmune peripheral neuropathy. Here, we took advantage of multiple NOD mouse strains congenic for Idd loci to test the role of these Idd loci the development of neuropathy and determine if B6 alleles at Idd loci that are protective for diabetes will also be for neuropathy. Thus, we generated NOD-B7-2KO strains congenic at Idd loci and examined the development of neuritis and clinical neuropathy. We found that the NOD-H-2(g7) MHC region is necessary for development of neuropathy in NOD-B7-2KO mice. In contrast, other Idd loci that significantly protect from diabetes did not affect neuropathy when considered individually. However, we found potent genetic interactions of some Idd loci that provided almost complete protection from neuritis and clinical neuropathy. In addition, defective immunoregulation by Tregs could supersede protection by some, but not other, Idd loci in a tissue-specific manner in a model where neuropathy and diabetes occurred concomitantly. Thus, our study helps identify Idd loci that control tissue-specific disease or confer general susceptibility to autoimmunity, and brings insight to the Treg-dependence of autoimmune processes influenced by given Idd region in the NOD background.


Assuntos
Diabetes Mellitus Tipo 1/genética , Loci Gênicos , Síndrome de Guillain-Barré/genética , Linfócitos T Reguladores/imunologia , Alelos , Animais , Antígeno B7-2/genética , Células Cultivadas , Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 1/imunologia , Feminino , Loci Gênicos/genética , Predisposição Genética para Doença/genética , Síndrome de Guillain-Barré/complicações , Síndrome de Guillain-Barré/imunologia , Antígenos de Histocompatibilidade Classe II/genética , Interferon gama/metabolismo , Masculino , Camundongos , Camundongos Congênicos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , Camundongos Knockout , Especificidade de Órgãos , Fatores Sexuais
7.
Cell Metab ; 25(4): 883-897.e8, 2017 Apr 04.
Artigo em Inglês | MEDLINE | ID: mdl-28380378

RESUMO

In cells experiencing unrelieved endoplasmic reticulum (ER) stress, the ER transmembrane kinase/endoribonuclease (RNase)-IRE1α-endonucleolytically degrades ER-localized mRNAs to promote apoptosis. Here we find that the ABL family of tyrosine kinases rheostatically enhances IRE1α's enzymatic activities, thereby potentiating ER stress-induced apoptosis. During ER stress, cytosolic ABL kinases localize to the ER membrane, where they bind, scaffold, and hyperactivate IRE1α's RNase. Imatinib-an anti-cancer tyrosine kinase inhibitor-antagonizes the ABL-IRE1α interaction, blunts IRE1α RNase hyperactivity, reduces pancreatic ß cell apoptosis, and reverses type 1 diabetes (T1D) in the non-obese diabetic (NOD) mouse model. A mono-selective kinase inhibitor that allosterically attenuates IRE1α's RNase-KIRA8-also efficaciously reverses established diabetes in NOD mice by sparing ß cells and preserving their physiological function. Our data support a model wherein ER-stressed ß cells contribute to their own demise during T1D pathogenesis and implicate the ABL-IRE1α axis as a drug target for the treatment of an autoimmune disease.


Assuntos
Diabetes Mellitus Tipo 1/metabolismo , Estresse do Retículo Endoplasmático , Endorribonucleases/metabolismo , Células Secretoras de Insulina/metabolismo , Células Secretoras de Insulina/patologia , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Proto-Oncogênicas c-abl/metabolismo , Transdução de Sinais , Animais , Apoptose/efeitos dos fármacos , Diabetes Mellitus Tipo 1/patologia , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Feminino , Humanos , Mesilato de Imatinib/farmacologia , Masculino , Camundongos Endogâmicos NOD , Modelos Biológicos , Ligação Proteica/efeitos dos fármacos , Pirimidinas/farmacologia , Ratos , Transdução de Sinais/efeitos dos fármacos , Resposta a Proteínas não Dobradas/efeitos dos fármacos
8.
Sci Transl Med ; 6(258): 258ra142, 2014 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-25320234

RESUMO

We examined the hypothesis that regulatory T cells (Tregs) modulate muscle injury and inflammation in the mdx mouse model of Duchenne muscular dystrophy (DMD). Although Tregs were largely absent in the muscle of wild-type mice and normal human muscle, they were present in necrotic lesions, displayed an activated phenotype, and showed increased expression of interleukin-10 (IL-10) in dystrophic muscle from mdx mice. Depletion of Tregs exacerbated muscle injury and the severity of muscle inflammation, which was characterized by an enhanced interferon-γ (IFN-γ) response and activation of M1 macrophages. To test the therapeutic value of targeting Tregs in muscular dystrophy, we treated mdx mice with IL-2/anti-IL-2 complexes and found that Tregs and IL-10 concentrations were increased in muscle, resulting in reduced expression of cyclooxygenase-2 and decreased myofiber injury. These findings suggest that Tregs modulate the progression of muscular dystrophy by suppressing type 1 inflammation in muscle associated with muscle fiber injury, and highlight the potential of Treg-modulating agents as therapeutics for DMD.


Assuntos
Inflamação/patologia , Músculo Esquelético/imunologia , Músculo Esquelético/patologia , Distrofia Muscular Animal/imunologia , Distrofia Muscular de Duchenne/imunologia , Distrofia Muscular de Duchenne/patologia , Linfócitos T Reguladores/imunologia , Animais , Progressão da Doença , Humanos , Interferon gama/metabolismo , Interleucina-10/metabolismo , Interleucina-2/metabolismo , Ativação Linfocitária/imunologia , Ativação de Macrófagos , Camundongos Endogâmicos mdx , Distrofia Muscular Animal/patologia , Fenótipo
10.
J Exp Med ; 206(3): 507-14, 2009 Mar 16.
Artigo em Inglês | MEDLINE | ID: mdl-19221395

RESUMO

Autoimmune-prone nonobese diabetic mice deficient for B7-2 spontaneously develop an autoimmune peripheral neuropathy mediated by inflammatory CD4(+) T cells that is reminiscent of Guillain-Barré syndrome and chronic inflammatory demyelinating polyneuropathy. To determine the etiology of this disease, CD4(+) T cell hybridomas were generated from inflamed tissue-derived CD4(+) T cells. A majority of T cell hybridomas were specific for myelin protein 0 (P0), which was the principal target of autoantibody responses targeting nerve proteins. To determine whether P0-specific T cell responses were sufficient to mediate disease, we generated a novel myelin P0-specific T cell receptor transgenic (POT) mouse. POT T cells were not tolerized or deleted during thymic development and proliferated in response to P0 in vitro. Importantly, when bred onto a recombination activating gene knockout background, POT mice developed a fulminant form of peripheral neuropathy that affected all mice by weaning age and led to their premature death by 3-5 wk of age. This abrupt disease was associated with the production of interferon gamma by P0-specific T cells and a lack of CD4(+) Foxp3(+) regulatory T cells. Collectively, our data suggest that myelin P0 is a major autoantigen in autoimmune peripheral neuropathy.


Assuntos
Doenças Autoimunes/imunologia , Doenças Autoimunes/patologia , Proteína P0 da Mielina/metabolismo , Doenças do Sistema Nervoso Periférico/imunologia , Doenças do Sistema Nervoso Periférico/patologia , Receptores de Antígenos de Linfócitos T alfa-beta/imunologia , Animais , Doenças Autoimunes/complicações , Linfócitos T CD4-Positivos/imunologia , Proliferação de Células , Citocinas/biossíntese , Epitopos , Hibridomas , Camundongos , Camundongos Endogâmicos NOD , Camundongos Transgênicos , Nervos Periféricos/imunologia , Nervos Periféricos/patologia , Doenças do Sistema Nervoso Periférico/complicações , Fenótipo
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