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1.
Immunity ; 2024 Aug 23.
Artigo em Inglês | MEDLINE | ID: mdl-39236718

RESUMO

Lymphocyte activation gene 3 (Lag3) is an inhibitory co-receptor expressed on activated T cells and has been proposed to regulate regulatory T (Treg) cell function. However, its precise modality and mechanisms remain elusive. We generated Treg cell-specific Lag3-mutant mouse models and found that Lag3 was essential for Treg cell control of autoimmunity. RNA sequencing analysis revealed that Lag3 mutation altered genes associated with metabolic processes, especially Myc target genes. Myc expression in Lag3-mutant Treg cells was increased to the level seen in conventional T helper (Th)1-type effector cells and directly correlated with their metabolic profiles and in vivo suppressive functions. The phosphatidylinositol 3-kinase (PI3K)-Akt-Rictor pathway was activated in Lag3-mutant Treg cells, and inhibiting PI3K, Rictor, or lactate dehydrogenase A (Ldha), a key Myc target enzyme converting pyruvate to lactate, was sufficient to restore normal metabolism and suppressive function in Lag3-mutant Treg cells. These findings indicate that Lag3 supports Treg cell suppression partly by tuning Myc-dependent metabolic programming.

2.
Physiol Rev ; 104(1): 473-532, 2024 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-37732829

RESUMO

The normal stress response in humans is governed by the hypothalamic-pituitary-adrenal (HPA) axis through heightened mechanisms during stress, raising blood levels of the glucocorticoid hormone cortisol. Glucocorticoids are quintessential compounds that balance the proper functioning of numerous systems in the mammalian body. They are also generated synthetically and are the preeminent therapy for inflammatory diseases. They act by binding to the nuclear receptor transcription factor glucocorticoid receptor (GR), which has two main isoforms (GRα and GRß). Our classical understanding of glucocorticoid signaling is from the GRα isoform, which binds the hormone, whereas GRß has no known ligands. With glucocorticoids being involved in many physiological and cellular processes, even small disruptions in their release via the HPA axis, or changes in GR isoform expression, can have dire ramifications on health. Long-term chronic glucocorticoid therapy can lead to a glucocorticoid-resistant state, and we deliberate how this impacts disease treatment. Chronic glucocorticoid treatment can lead to noticeable side effects such as weight gain, adiposity, diabetes, and others that we discuss in detail. There are sexually dimorphic responses to glucocorticoids, and women tend to have a more hyperresponsive HPA axis than men. This review summarizes our understanding of glucocorticoids and critically analyzes the GR isoforms and their beneficial and deleterious mechanisms and the sexual differences that cause a dichotomy in responses. We also discuss the future of glucocorticoid therapy and propose a new concept of dual GR isoform agonist and postulate why activating both isoforms may prevent glucocorticoid resistance.


Assuntos
Glucocorticoides , Sistema Hipotálamo-Hipofisário , Masculino , Animais , Feminino , Humanos , Glucocorticoides/metabolismo , Sistema Hipotálamo-Hipofisário/metabolismo , Caracteres Sexuais , Sistema Hipófise-Suprarrenal/metabolismo , Receptores de Glucocorticoides/metabolismo , Isoformas de Proteínas/metabolismo , Mamíferos/metabolismo
3.
Immunity ; 53(3): 581-596.e5, 2020 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-32707034

RESUMO

Glucocorticoids (GC) are the mainstay treatment option for inflammatory conditions. Despite the broad usage of GC, the mechanisms by which GC exerts its effects remain elusive. Here, utilizing murine autoimmune and allergic inflammation models, we report that Foxp3+ regulatory T (Treg) cells are irreplaceable GC target cells in vivo. Dexamethasone (Dex) administered in the absence of Treg cells completely lost its ability to control inflammation, and the lack of glucocorticoid receptor in Treg cells alone resulted in the loss of therapeutic ability of Dex. Mechanistically, Dex induced miR-342-3p specifically in Treg cells and miR-342-3p directly targeted the mTORC2 component, Rictor. Altering miRNA-342-3p or Rictor expression in Treg cells dysregulated metabolic programming in Treg cells, controlling their regulatory functions in vivo. Our results uncover a previously unknown contribution of Treg cells during glucocorticoid-mediated treatment of inflammation and the underlying mechanisms operated via the Dex-miR-342-Rictor axis.


Assuntos
Dexametasona/farmacologia , Glucocorticoides/farmacologia , Inflamação/tratamento farmacológico , MicroRNAs/genética , Proteína Companheira de mTOR Insensível à Rapamicina/metabolismo , Linfócitos T Reguladores/imunologia , Animais , Anti-Inflamatórios/farmacologia , Fatores de Transcrição Forkhead/metabolismo , Alvo Mecanístico do Complexo 2 de Rapamicina/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , MicroRNAs/biossíntese , Receptores de Glucocorticoides/genética , Linfócitos T Reguladores/metabolismo
4.
Nat Immunol ; 17(5): 583-92, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-26998763

RESUMO

Interleukin 1ß (IL-1ß) is critical for the in vivo survival, expansion and effector function of IL-17-producing helper T (T(H)17) cells during autoimmune responses, including experimental autoimmune encephalomyelitis (EAE). However, the spatiotemporal role and cellular source of IL-1ß during EAE pathogenesis are poorly defined. In the present study, we uncovered a T cell-intrinsic inflammasome that drives IL-1ß production during T(H)17-mediated EAE pathogenesis. Activation of T cell antigen receptors induced expression of pro-IL-1ß, whereas ATP stimulation triggered T cell production of IL-1ß via ASC-NLRP3-dependent caspase-8 activation. IL-1R was detected on T(H)17 cells but not on type 1 helper T (T(H)1) cells, and ATP-treated T(H)17 cells showed enhanced survival compared with ATP-treated T(H)1 cells, suggesting autocrine action of T(H)17-derived IL-1ß. Together these data reveal a critical role for IL-1ß produced by a T(H)17 cell-intrinsic ASC-NLRP3-caspase-8 inflammasome during inflammation of the central nervous system.


Assuntos
Proteínas Reguladoras de Apoptose/imunologia , Encefalomielite Autoimune Experimental/imunologia , Linfócitos T/imunologia , Células Th17/imunologia , Trifosfato de Adenosina/farmacologia , Animais , Proteínas Reguladoras de Apoptose/genética , Proteínas Reguladoras de Apoptose/metabolismo , Proteínas Adaptadoras de Sinalização CARD , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Proteínas de Transporte/genética , Proteínas de Transporte/imunologia , Proteínas de Transporte/metabolismo , Caspase 8/genética , Caspase 8/imunologia , Caspase 8/metabolismo , Sobrevivência Celular/genética , Sobrevivência Celular/imunologia , Células Cultivadas , Encefalomielite Autoimune Experimental/genética , Encefalomielite Autoimune Experimental/metabolismo , Citometria de Fluxo , Expressão Gênica/imunologia , Immunoblotting , Inflamassomos/genética , Inflamassomos/imunologia , Inflamassomos/metabolismo , Interleucina-17/genética , Interleucina-17/imunologia , Interleucina-17/metabolismo , Interleucina-1beta/genética , Interleucina-1beta/imunologia , Interleucina-1beta/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Proteína 3 que Contém Domínio de Pirina da Família NLR , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transdução de Sinais/genética , Transdução de Sinais/imunologia , Linfócitos T/efeitos dos fármacos , Linfócitos T/metabolismo , Células Th17/efeitos dos fármacos , Células Th17/metabolismo
5.
J Immunol ; 212(12): 1867-1876, 2024 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-38647384

RESUMO

Allergic airway inflammation results from uncontrolled immune responses to environmental Ags. Although it is well established that allergic immune responses exhibit a high degree of diversity, driven by primary effector cell types such as eosinophils, neutrophils, or CD4 T cells with distinct effector signatures, the mechanisms responsible for such pathogenesis remain elusive. Foxp3+ regulatory T cells (Tregs) are essential immune regulators during chronic inflammation, including allergic airway inflammation. Emerging evidence suggests that Tregs infiltrating inflamed tissues exhibit distinct phenotypes dependent on the specific tissue sites and can display heterogeneity and tissue residency. Whether diverse allergic airway inflammatory responses influence infiltrating Treg heterogeneity or Treg lung residency has not been explored. We employed an unbiased single-cell RNA sequencing approach to investigate lung-infiltrating Tregs in models of eosinophilic and neutrophilic airway inflammation. We found that lung-infiltrating Tregs are highly heterogeneous, and that Tregs displaying lung-resident phenotypes are significantly different depending on the types of inflammation. Treg expression of ST2, a receptor for alarmin IL-33, was predominantly associated with eosinophilic inflammation and tissue residency. Nevertheless, Treg-specific ST2 deficiency did not affect the development of eosinophilic allergic inflammation or the generation of lung-resident Tregs. These results uncover a stark heterogeneity among Tregs infiltrating the lungs during allergic airway inflammation. The results indicate that varying types of inflammation may give rise to phenotypically distinct lung-resident Tregs, underscoring a (to our knowledge) novel mechanism by which inflammatory cues may shape the composition of infiltrating Tregs, allowing them to regulate inflammatory responses through tissue-adapted mechanisms.


Assuntos
Eosinófilos , Pulmão , Neutrófilos , Análise de Célula Única , Linfócitos T Reguladores , Linfócitos T Reguladores/imunologia , Animais , Camundongos , Neutrófilos/imunologia , Eosinófilos/imunologia , Pulmão/imunologia , Pulmão/patologia , Camundongos Endogâmicos C57BL , Proteína 1 Semelhante a Receptor de Interleucina-1/genética , Proteína 1 Semelhante a Receptor de Interleucina-1/imunologia , Camundongos Knockout , Inflamação/imunologia , Modelos Animais de Doenças , Interleucina-33/imunologia , Eosinofilia/imunologia , Eosinofilia/patologia
6.
Immunity ; 45(6): 1179-1181, 2016 12 20.
Artigo em Inglês | MEDLINE | ID: mdl-28002723

RESUMO

Exfoliating infected bladder epithelium is a powerful host defense mechanism that reduces bacterial burden. In this issue of Immunity, Choi et al. (2016) present a function of mast cells that orchestrates the infected epithelial cell exfoliation via cytolytic granules.


Assuntos
Mastócitos , Bexiga Urinária/imunologia , Células Epiteliais/imunologia , Humanos
7.
J Immunol ; 210(6): 721-731, 2023 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-36695771

RESUMO

Besides antiviral functions, type I IFN expresses potent anti-inflammatory properties and is being widely used to treat certain autoimmune conditions, such as multiple sclerosis. In a murine model of multiple sclerosis, experimental autoimmune encephalomyelitis, administration of IFN-ß effectively attenuates the disease development. However, the precise mechanisms underlying IFN-ß-mediated treatment remain elusive. In this study, we report that IFN-induced protein with tetratricopeptide repeats 2 (Ifit2), a type I and type III IFN-stimulated gene, plays a previously unrecognized immune-regulatory role during autoimmune neuroinflammation. Mice deficient in Ifit2 displayed greater susceptibility to experimental autoimmune encephalomyelitis and escalated immune cell infiltration in the CNS. Ifit2 deficiency was also associated with microglial activation and increased myeloid cell infiltration. We also observed that myelin debris clearance and the subsequent remyelination were substantially impaired in Ifit2-/- CNS tissues. Clearing myelin debris is an important function of the reparative-type myeloid cell subset to promote remyelination. Indeed, we observed that bone marrow-derived macrophages, CNS-infiltrating myeloid cells, and microglia from Ifit2-/- mice express cytokine and metabolic genes associated with proinflammatory-type myeloid cell subsets. Taken together, our findings uncover a novel regulatory function of Ifit2 in autoimmune inflammation in part by modulating myeloid cell function and metabolic activity.


Assuntos
Encefalomielite Autoimune Experimental , Esclerose Múltipla , Animais , Camundongos , Inflamação , Camundongos Endogâmicos C57BL , Microglia , Células Mieloides , Repetições de Tetratricopeptídeos , Interferons/farmacologia
8.
Proc Natl Acad Sci U S A ; 119(3)2022 01 18.
Artigo em Inglês | MEDLINE | ID: mdl-35022243

RESUMO

Recent studies have identified a critical role for B cell-produced cytokines in regulating both humoral and cellular immunity. Here, we show that B cells are an essential source of interleukin-27 (IL-27) during persistent lymphocytic choriomeningitis virus (LCMV) clone 13 (Cl-13) infection. By using conditional knockout mouse models with specific IL-27p28 deletion in B cells, we observed that B cell-derived IL-27 promotes survival of virus-specific CD4 T cells and supports functions of T follicular helper (Tfh) cells. Mechanistically, B cell-derived IL-27 promotes CD4 T cell function, antibody class switch, and the ability to control persistent LCMV infection. Deletion of IL-27ra in T cells demonstrated that T cell-intrinsic IL-27R signaling is essential for viral control, optimal CD4 T cell responses, and antibody class switch during persistent LCMV infection. Collectively, our findings identify a cellular mechanism whereby B cell-derived IL-27 drives antiviral immunity and antibody responses through IL-27 signaling on T cells to promote control of LCMV Cl-13 infection.


Assuntos
Linfócitos B/metabolismo , Interleucina-27/metabolismo , Coriomeningite Linfocítica/imunologia , Imunidade Adaptativa , Animais , Anticorpos Antivirais , Linfócitos T CD4-Positivos/imunologia , Citocinas/metabolismo , Imunidade Celular , Interleucina-27/genética , Interleucinas , Vírus da Coriomeningite Linfocítica/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout
9.
J Immunol ; 207(3): 765-770, 2021 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-34301840

RESUMO

Glucocorticoids are a highly effective first-line treatment option for many inflammatory diseases, including asthma. Some patients develop a steroid-resistant condition, yet, the cellular and molecular mechanisms underlying steroid resistance remain largely unknown. In this study, we used a murine model of steroid-resistant airway inflammation and report that combining systemic dexamethasone and intranasal IL-27 is able to reverse the inflammation. Foxp3+ regulatory T cells (Tregs) were required during dexamethasone/IL-27 treatment of steroid-resistant allergic inflammation, and importantly, direct stimulation of Tregs via glucocorticoid or IL-27 receptors was essential. Mechanistically, IL-27 stimulation in Tregs enhanced expression of the agonistic glucocorticoid receptor-α isoform. Overexpression of inhibitory glucocorticoid receptor-ß isoform in Tregs alone was sufficient to elicit steroid resistance in a steroid-sensitive allergic inflammation model. Taken together, our results demonstrate for the first time, to our knowledge, that Tregs are instrumental during steroid resistance and that manipulating steroid responsiveness in Tregs may represent a novel strategy to treat steroid refractory asthma.


Assuntos
Asma/imunologia , Dexametasona/uso terapêutico , Interleucina-27/uso terapêutico , Hipersensibilidade Respiratória/imunologia , Linfócitos T Reguladores/imunologia , Alérgenos/imunologia , Animais , Asma/tratamento farmacológico , Células Cultivadas , Modelos Animais de Doenças , Resistência a Medicamentos , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/metabolismo , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Ovalbumina/imunologia , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Receptores de Glucocorticoides/genética , Receptores de Glucocorticoides/metabolismo , Hipersensibilidade Respiratória/tratamento farmacológico
10.
Proc Natl Acad Sci U S A ; 116(14): 6932-6937, 2019 04 02.
Artigo em Inglês | MEDLINE | ID: mdl-30894497

RESUMO

Clinical application of inhaled glucocorticoids (GCs) has been hampered in the case of steroid-resistant severe asthma. To overcome this limitation, we have developed a series of highly potent GCs, including VSGC12, VSG158, and VSG159 based on the structural insight into the glucocorticoid receptor (GR). Particularly, VSG158 exhibits a maximal repression of lung inflammation and is 10 times more potent than the currently most potent clinical GC, Fluticasone Furoate (FF), in a murine model of asthma. More importantly, VSG158 displays a unique property to reduce neutrophilic inflammation in a steroid-resistant airway inflammation model, which is refractory to clinically available GCs, including dexamethasone and FF. VSG158 and VSG159 are able to deliver effective treatments with reduced off-target and side effects. In addition, these GCs also display pharmacokinetic properties that are suitable for the inhalation delivery method for asthma treatment. Taken together, the excellent therapeutic and side-effect profile of these highly potent GCs holds promise for treating steroid-resistant severe asthma.


Assuntos
Antiasmáticos , Asma/tratamento farmacológico , Desenvolvimento de Medicamentos , Glucocorticoides , Animais , Antiasmáticos/química , Antiasmáticos/farmacologia , Asma/patologia , Modelos Animais de Doenças , Feminino , Glucocorticoides/química , Glucocorticoides/farmacologia , Masculino , Camundongos , Receptores de Glucocorticoides/agonistas , Índice de Gravidade de Doença
11.
Immunity ; 36(5): 821-33, 2012 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-22608496

RESUMO

Interleukin-25 (IL-25 or IL-17E), a member of the structurally related IL-17 family, functions as an important mediator of T helper 2 cell-type (type 2) responses. We examined the cell type-specific role of IL-25-induced Act1-mediated signaling in protective immunity against helminth infection. Targeted Act1 deficiency in epithelial cells resulted in a marked delay in worm expulsion and abolished the expansion of the Lin(-)c-Kit(+) innate cell population in the mesenteric lymph node, lung, and liver. Th2 cell-inducing cytokine (IL-25 and IL-33) expression were reduced in the intestinal epithelial cells from the infected and IL-25-injected epithelial-specific Act1-deficient mice. Adoptive transfer of Lin(-)c-Kit(+) cells or combined injection of IL-25 and IL-33 restored the type 2 responses in these mice. Taken together, these results suggest that epithelial-specific Act1 mediates the expansion of the Lin(-)c-Kit(+) innate cell population through the positive-feedback loop of IL-25, initiating the type 2 immunity against helminth infection.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/imunologia , Células Epiteliais/imunologia , Helmintíase/imunologia , Helmintos/imunologia , Interleucinas/imunologia , Células Th2/imunologia , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Linhagem da Célula , Células Cultivadas , Células Epiteliais/citologia , Células Epiteliais/metabolismo , Helmintíase/metabolismo , Helmintos/metabolismo , Imunidade Inata/imunologia , Interleucinas/metabolismo , Mucosa Intestinal/citologia , Mucosa Intestinal/imunologia , Mucosa Intestinal/metabolismo , Fígado/citologia , Fígado/imunologia , Fígado/metabolismo , Pulmão/citologia , Pulmão/imunologia , Pulmão/metabolismo , Linfonodos/imunologia , Linfonodos/metabolismo , Macrófagos/imunologia , Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Células Th2/metabolismo
12.
J Immunol ; 202(6): 1680-1685, 2019 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-30700587

RESUMO

IL-27 regulates immune responses in inflammation. The underlying mechanism of IL-27 functions has long been attributed to its ability to induce IL-10 production in activated CD4 T cells. In this study, we report that Foxp3+ regulatory T cells (Tregs) are the main target cells of IL-27, mediating its immunoregulatory functions in vivo. Systemically delivered IL-27 efficiently prevents the development of experimental autoimmune encephalomyelitis, an autoimmune inflammation in the CNS. However, it failed to do so upon Treg depletion. IL-27 signaling in Tregs was necessary, as transferring Tregs deficient in IL-27Rα or Lag3, a downstream molecule induced by IL-27, was unable to protect mice from experimental autoimmune encephalomyelitis. IL-27 efficiently induced IL-10 expression in CD4 T cells in vitro; however, we found no evidence supporting IL-27-induced IL-10 induction in CD4 T cells in vivo. Taken together, our results uncover an irreplaceable contribution of Tregs during IL-27-mediated control of inflammation.


Assuntos
Antígenos CD/imunologia , Autoimunidade/imunologia , Encefalomielite Autoimune Experimental/imunologia , Inflamação/imunologia , Interleucinas/imunologia , Linfócitos T Reguladores/imunologia , Animais , Interleucina-10/imunologia , Ativação Linfocitária/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteína do Gene 3 de Ativação de Linfócitos
13.
Nat Immunol ; 9(12): 1333-9, 2008 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-19008933

RESUMO

Basophils, the least abundant granulocytes, have poorly understood functions. They have been linked to the development of T helper type 2 immunity during parasite infection and allergic inflammation. Emerging evidence has not only shown the critical involvement of basophils in the development of T helper type 2 immunity but also provided useful animal models with which basophil functions can be further examined. However, distinctions must be made between what basophils 'can do' after in vitro manipulation and what they 'actually do' during in vivo immune responses; these may be very different. In this review, the functions of basophils determined on the basis of analysis of in vitro and in vivo systems and their potential involvement in clinical settings are discussed.


Assuntos
Basófilos/imunologia , Animais , Humanos
14.
Proc Natl Acad Sci U S A ; 114(38): 10190-10195, 2017 09 19.
Artigo em Inglês | MEDLINE | ID: mdl-28874534

RESUMO

Dysregulated Foxp3+ Treg functions result in uncontrolled immune activation and autoimmunity. Therefore, identifying cellular factors modulating Treg functions is an area of great importance. Here, using Treg-specific Il27ra-/- mice, we report that IL-27 signaling in Foxp3+ Tregs is essential for Tregs to control autoimmune inflammation in the central nervous system (CNS). Following experimental autoimmune encephalomyelitis (EAE) induction, Treg-specific Il27ra-/- mice develop more severe EAE. Consistent with the severe disease, the numbers of IFNγ- and IL-17-producing CD4 T cells infiltrating the CNS tissues are greater in these mice. Treg accumulation in the inflamed CNS tissues is not affected by the lack of IL-27 signaling in Tregs, suggesting a functional defect of Il27ra-/- Tregs. IL-10 production by conventional CD4 T cells and their CNS accumulation are rather elevated in Treg-specific Il27ra-/- mice. Analysis with Treg fate-mapping reporter mice further demonstrates that IL-27 signaling in Tregs may control stability of Foxp3 expression. Finally, systemic administration of recombinant IL-27 in Treg-specific Il27ra-/- mice fails to ameliorate the disease even in the presence of IL-27-responsive conventional CD4 T cells. These findings uncover a previously unknown role of IL-27 in regulating Treg function to control autoimmune inflammation.


Assuntos
Doenças Autoimunes/imunologia , Encefalomielite/imunologia , Receptores de Citocinas/metabolismo , Linfócitos T Reguladores/metabolismo , Animais , Doenças Autoimunes/tratamento farmacológico , Sistema Nervoso Central/imunologia , Avaliação Pré-Clínica de Medicamentos , Encefalomielite/tratamento farmacológico , Fatores de Transcrição Forkhead/metabolismo , Interleucinas/metabolismo , Interleucinas/uso terapêutico , Camundongos Transgênicos , Receptores de Citocinas/genética , Receptores de Interleucina
15.
Immunity ; 32(1): 54-66, 2010 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-20060329

RESUMO

Interleukin-1 (IL-1)-mediated signaling in T cells is essential for T helper 17 (Th17) cell differentiation. We showed here that SIGIRR, a negative regulator of IL-1 receptor and Toll-like receptor signaling, was induced during Th17 cell lineage commitment and governed Th17 cell differentiation and expansion through its inhibitory effects on IL-1 signaling. The absence of SIGIRR in T cells resulted in increased Th17 cell polarization in vivo upon myelin oligodendrocyte glycoprotein (MOG(35-55)) peptide immunization. Recombinant IL-1 promoted a marked increase in the proliferation of SIGIRR-deficient T cells under an in vitro Th17 cell-polarization condition. Importantly, we detected increased IL-1-induced phosphorylation of JNK and mTOR kinase in SIGIRR-deficient Th17 cells compared to wild-type Th17 cells. IL-1-induced proliferation was abolished in mTOR-deficient Th17 cells, indicating the essential role of mTOR activation. Our results demonstrate an important mechanism by which SIGIRR controls Th17 cell expansion and effector function through the IL-1-induced mTOR signaling pathway.


Assuntos
Diferenciação Celular/imunologia , Interleucina-17/imunologia , Peptídeos e Proteínas de Sinalização Intracelular/imunologia , Proteínas Serina-Treonina Quinases/imunologia , Receptores de Interleucina-1/imunologia , Linfócitos T Auxiliares-Indutores/citologia , Animais , Linhagem da Célula/imunologia , Proliferação de Células , Separação Celular , Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/patologia , Ativação Enzimática/imunologia , Ensaio de Imunoadsorção Enzimática , Citometria de Fluxo , Immunoblotting , Imunoprecipitação , Interleucina-17/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Camundongos , Camundongos Knockout , Proteínas Serina-Treonina Quinases/metabolismo , Receptores de Interleucina-1/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transdução de Sinais/imunologia , Subpopulações de Linfócitos T/citologia , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Linfócitos T Auxiliares-Indutores/imunologia , Linfócitos T Auxiliares-Indutores/metabolismo , Serina-Treonina Quinases TOR , Transfecção
16.
J Immunol ; 198(2): 908-915, 2017 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-27927968

RESUMO

γδ T lymphocytes, dominant T cell subsets in the intestine, mediate both regulatory and pathogenic roles, yet the mechanisms underlying such opposing effects remain unclear. In this study, we identified a unique γδ T cell subset that coexpresses high levels of gut-homing integrins, CD103 and α4ß7. They were exclusively found in the mesenteric lymph node after T cell-mediated colitis induction, and their appearance preceded the inflammation. Adoptive transfer of the CD103+α4ß7high subsets enhanced Th1/Th17 T cell generation and accumulation in the intestine, and the disease severity. The level of generation correlated with the disease severity. Moreover, these cells were also found to be elevated in a spontaneous mouse model of ileitis. Based on the procolitogenic function, we referred to this subset as "inflammatory" γδ T cells. Targeting inflammatory γδ T cells may open a novel strategy to treat inflammatory diseases where γδ T cells play a pathogenic role including inflammatory bowel disease.


Assuntos
Antígenos CD/imunologia , Doenças Inflamatórias Intestinais/imunologia , Cadeias alfa de Integrinas/imunologia , Integrinas/imunologia , Subpopulações de Linfócitos T/imunologia , Transferência Adotiva , Animais , Modelos Animais de Doenças , Citometria de Fluxo , Perfilação da Expressão Gênica , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores de Antígenos de Linfócitos T gama-delta/imunologia , Receptores de Retorno de Linfócitos/imunologia , Transcriptoma
17.
J Immunol ; 199(12): 3943-3951, 2017 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-29093062

RESUMO

Understanding functions of Foxp3+ regulatory T cells (Tregs) during allergic airway inflammation remains incomplete. In this study, we report that, during cockroach Ag-induced allergic airway inflammation, Foxp3+ Tregs are rapidly mobilized into the inflamed lung tissues. However, the level of Treg accumulation in the lung was different depending on the type of inflammation. During eosinophilic airway inflammation, ∼30% of lung-infiltrating CD4 T cells express Foxp3, indicative of Tregs. On the contrary, only ∼10% of infiltrating CD4 T cells express Foxp3 during neutrophilic airway inflammation. Despite the different accumulation, the lung inflammation and inflammatory T cell responses were aggravated following Treg depletion, regardless of the type of inflammation, suggesting regulatory roles for Tregs. Interestingly, however, the extent to which inflammatory responses are aggravated by Treg depletion was significantly greater during eosinophilic airway inflammation. Indeed, lung-infiltrating Tregs exhibit phenotypic and functional features associated with potent suppression. Our results demonstrate that Tregs are essential regulators of inflammation, regardless of the type of inflammation, although the mechanisms used by Tregs to control inflammation may be shaped by environmental cues available to them.


Assuntos
Alveolite Alérgica Extrínseca/imunologia , Pulmão/imunologia , Infiltração de Neutrófilos/imunologia , Eosinofilia Pulmonar/imunologia , Linfócitos T Reguladores/imunologia , Adjuvantes Imunológicos/administração & dosagem , Adjuvantes Imunológicos/toxicidade , Alérgenos/administração & dosagem , Alérgenos/imunologia , Compostos de Alúmen/administração & dosagem , Compostos de Alúmen/toxicidade , Alveolite Alérgica Extrínseca/etiologia , Alveolite Alérgica Extrínseca/patologia , Animais , Baratas/imunologia , Modelos Animais de Doenças , Fatores de Transcrição Forkhead/análise , Adjuvante de Freund/administração & dosagem , Adjuvante de Freund/toxicidade , Perfilação da Expressão Gênica , Genes Reporter , Imunofenotipagem , Inflamação , Proteínas de Insetos/administração & dosagem , Proteínas de Insetos/imunologia , Pulmão/patologia , Camundongos Endogâmicos C57BL , Eosinofilia Pulmonar/etiologia , Eosinofilia Pulmonar/patologia , Organismos Livres de Patógenos Específicos
18.
Bioprocess Biosyst Eng ; 42(8): 1247-1254, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31030377

RESUMO

The performance of an air-cathode microbial fuel cell (MFC) with a cap arrangement was significantly affected by humidity conditions in the cathode. An MFC at a relative humidity (RH) of 88% produced a highest cell voltage of 0.42 V (600 Ω) compared to other operations at 50% (0.34 V) and 30% (0.29 V) RHs. During polarization analysis, MFC operation at 88% RH produced a maximum power density of 0.377 W/m2 (a current density of 1.5 A/m2), which was 1.8 and 2.9 times higher than with 50% and 30% RHs, respectively. Cyclic voltammogram analysis revealed a higher reduction current of - 0.073 A with 88% RH. Furthermore, no increase in dissolved oxygen concentration in the anode chamber was observed with 88% RH. This result suggests that control of humidity conditions in cathode chamber could maximize power generation from an air-cathode MFC.


Assuntos
Ar , Fontes de Energia Bioelétrica , Eletricidade , Umidade , Oxigênio/química , Eletrodos
19.
Eur J Immunol ; 46(2): 340-6, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26549797

RESUMO

T cells expressing the γδ TCR are dominant T-cell subsets in the intestinal immune system. We previously demonstrated that γδ T cells play important roles in augmenting Th17-type colitogenic immune responses in a T-cell-induced colitic inflammation model. However, its underlying mechanism remains poorly understood. In this study, an in vitro coculture system using effector T cells enriched in gut Ag-reactive cells was employed as a readout tool to search for gut Ag presenting APCs. We found that the presence of γδ T cells dramatically enhances gut Ag presentation within the mLN in mice. Gut Ag presentation by CD11b(+) DC subsets was particularly controlled by γδ T cells. Interestingly, γδ T-cell entry to the lymph nodes was essential to improve the Ag presentation. Therefore, our results highlight that γδ T cells play a previously unrecognized role to support colitogenic immunity by regulating gut Ag presentation in the draining LN.


Assuntos
Colite/imunologia , Células Dendríticas/imunologia , Intestinos/imunologia , Receptores de Antígenos de Linfócitos T gama-delta/metabolismo , Subpopulações de Linfócitos T/metabolismo , Células Th17/imunologia , Animais , Apresentação de Antígeno , Células Cultivadas , Modelos Animais de Doenças , Humanos , Imunidade nas Mucosas , Linfonodos/imunologia , Mesentério/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout
20.
Immunity ; 29(4): 551-64, 2008 Oct 17.
Artigo em Inglês | MEDLINE | ID: mdl-18957266

RESUMO

The physiologic control of cytokine receptor activation is primarily mediated by reciprocal activation of receptor-associated protein tyrosine kinases and protein tyrosine phosphatases (PTPs). Here, we show that immediately after ligand-dependent activation, interleukin (IL)-4 receptor generated reactive oxygen species (ROS) via phosphatidylinositol 3-kinase-dependent activation of NAD(P)H oxidase (NOX)1 and NOX5L. ROS, in turn, promoted IL-4 receptor activation by oxidatively inactivating PTP1B that physically associated with and deactivated IL-4 receptor. However, ROS were not required for the initiation of IL-4 receptor activation. ROS generated by other cytokine receptors, including those for erythropoietin, tumor necrosis factor-alpha, or IL-3, also promoted IL-4 signaling. These data indicate that inactivation of receptor-associated PTP activity by cytokine-generated ROS is a physiologic mechanism for the amplification of cytokine receptor activation in both cis and trans, revealing a role for ROS in cytokine crosstalk.


Assuntos
Interleucina-4/metabolismo , NADPH Oxidases/metabolismo , Proteína Tirosina Fosfatase não Receptora Tipo 1/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Receptores de Interleucina-4/metabolismo , Animais , Linhagem Celular , Linhagem Celular Tumoral , Clonagem Molecular , Humanos , Camundongos , Oxirredução , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Receptor de Insulina/metabolismo , Transdução de Sinais
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