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1.
Gut ; 73(1): 92-104, 2023 Dec 07.
Artigo em Inglês | MEDLINE | ID: mdl-37595983

RESUMO

OBJECTIVE: Wheat has become a main staple globally. We studied the effect of defined pro-inflammatory dietary proteins, wheat amylase trypsin inhibitors (ATI), activating intestinal myeloid cells via toll-like receptor 4, in experimental autoimmune encephalitis (EAE), a model of multiple sclerosis (MS). DESIGN: EAE was induced in C57BL/6J mice on standardised dietary regimes with defined content of gluten/ATI. Mice received a gluten and ATI-free diet with defined carbohydrate and protein (casein/zein) content, supplemented with: (a) 25% of gluten and 0.75% ATI; (b) 25% gluten and 0.19% ATI or (c) 1.5% purified ATI. The effect of dietary ATI on clinical EAE severity, on intestinal, mesenteric lymph node, splenic and central nervous system (CNS) subsets of myeloid cells and lymphocytes was analysed. Activation of peripheral blood mononuclear cells from patients with MS and healthy controls was compared. RESULTS: Dietary ATI dose-dependently caused significantly higher EAE clinical scores compared with mice on other dietary regimes, including on gluten alone. This was mediated by increased numbers and activation of pro-inflammatory intestinal, lymph node, splenic and CNS myeloid cells and of CNS-infiltrating encephalitogenic T-lymphocytes. Expectedly, ATI activated peripheral blood monocytes from both patients with MS and healthy controls. CONCLUSIONS: Dietary wheat ATI activate murine and human myeloid cells. The amount of ATI present in an average human wheat-based diet caused mild intestinal inflammation, which was propagated to extraintestinal sites, leading to exacerbation of CNS inflammation and worsening of clinical symptoms in EAE. These results support the importance of the gut-brain axis in inflammatory CNS disease.


Assuntos
Esclerose Múltipla , Humanos , Animais , Camundongos , Inibidores da Tripsina/farmacologia , Inibidores da Tripsina/química , Triticum/química , Amilases , Leucócitos Mononucleares , Camundongos Endogâmicos C57BL , Inflamação , Sistema Nervoso Central , Glutens , Dieta
2.
Cell Rep ; 42(4): 112378, 2023 04 25.
Artigo em Inglês | MEDLINE | ID: mdl-37060566

RESUMO

The signals controlling marginal zone (MZ) and follicular (FO) B cell development remain incompletely understood. Here, we show that AKT orchestrates MZ B cell formation in mice and humans. Genetic models that increase AKT signaling in B cells or abolish its impact on FoxO transcription factors highlight the AKT-FoxO axis as an on-off switch for MZ B cell formation in mice. In humans, splenic immunoglobulin (Ig) D+CD27+ B cells, proposed as an MZ B cell equivalent, display higher AKT signaling than naive IgD+CD27- and memory IgD-CD27+ B cells and develop in an AKT-dependent manner from their precursors in vitro, underlining the conservation of this developmental pathway. Consistently, CD148 is identified as a receptor indicative of the level of AKT signaling in B cells, expressed at a higher level in MZ B cells than FO B cells in mice as well as humans.


Assuntos
Linfócitos B , Proteínas Proto-Oncogênicas c-akt , Humanos , Camundongos , Animais , Tecido Linfoide , Transdução de Sinais , Baço
3.
Cell Rep ; 38(13): 110565, 2022 03 29.
Artigo em Inglês | MEDLINE | ID: mdl-35354043

RESUMO

Interleukin (IL)-10 is considered a prototypical anti-inflammatory cytokine, significantly contributing to the maintenance and reestablishment of immune homeostasis. Accordingly, it has been shown in the intestine that IL-10 produced by Tregs can act on effector T cells, thereby limiting inflammation. Herein, we investigate whether this role also applies to IL-10 produced by T cells during central nervous system (CNS) inflammation. During neuroinflammation, both CNS-resident and -infiltrating cells produce IL-10; yet, as IL-10 has a pleotropic function, the exact contribution of the different cellular sources is not fully understood. We find that T-cell-derived IL-10, but not other relevant IL-10 sources, can promote inflammation in experimental autoimmune encephalomyelitis. Furthermore, in the CNS, T-cell-derived IL-10 acts on effector T cells, promoting their survival and thereby enhancing inflammation and CNS autoimmunity. Our data indicate a pro-inflammatory role of T-cell-derived IL-10 in the CNS.


Assuntos
Interleucina-10 , Linfócitos T , Animais , Linfócitos T CD4-Positivos , Sobrevivência Celular , Sistema Nervoso Central , Inflamação , Interleucina-10/fisiologia , Camundongos
4.
J Invest Dermatol ; 142(3 Pt A): 559-570.e6, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-34536483

RESUMO

Jak inhibitors are increasingly used in dermatology. Despite broad inhibitory effects on cytokine signaling cascades, they only modestly increase the risk for infectious diseases. To address the molecular mechanisms underlying this unexpected clinical observation, we investigated how tofacintib (tofa), a first-in-class Jak inhibitor, regulates host defense responses in toll-like receptor 4-activated human macrophages. Specifically, we asked whether tofa inhibits anti-inflammatory IL-10 signaling, thereby counteracting the downregulation of inflammatory, host-protective pathways. We found that tofa blocked macrophage responses to IL-10 at the level of signal transducer and activator of transcription 3 phosphorylation. Furthermore, toll-like receptor 4-induced, autocrine/paracrine IL-10/IL-10R activation promoted the expression of hepcidin, the master regulator of iron metabolism, resulting in intracellular iron sequestration. In contrast, autocrine/paracrine IL-10/IL-10R activation repressed the expression of cathelicidin antimicrobial peptide as well as antigen-presenting molecules, thus together, inducing a pathogen-favoring environment. Although tofa further repressed cathelicidin, it prevented the induction of intracellular HAMP and restored the expression of antigen-presentation molecules in toll-like receptor 4-activated macrophages. Our study supports the concept that induction of IL-10/IL-10R signaling drives a complex immune evasion strategy of intracellular microbes. Moreover, we conclude that tofa has diverging effects on macrophage host response pathways, and we identify the toll-like receptor 4-IL-10-signal transducer and activator of transcription 3-HAMP axis as a potential therapeutic target to counteract immune evasion.


Assuntos
Inibidores de Janus Quinases , Receptor 4 Toll-Like , Humanos , Interleucina-10/metabolismo , Ferro/metabolismo , Inibidores de Janus Quinases/farmacologia , Macrófagos/metabolismo , Piperidinas , Pirimidinas , Fator de Transcrição STAT3/metabolismo , Receptor 4 Toll-Like/metabolismo
6.
Sci Immunol ; 6(56)2021 02 05.
Artigo em Inglês | MEDLINE | ID: mdl-33547052

RESUMO

Interleukin-17A- (IL-17A) and IL-17F-producing CD4+ T helper cells (TH17 cells) are implicated in the development of chronic inflammatory diseases, such as multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis (EAE). TH17 cells also orchestrate leukocyte invasion of the central nervous system (CNS) and subsequent tissue damage. However, the role of IL-17A and IL-17F as effector cytokines is still confused with the encephalitogenic function of the cells that produce these cytokines, namely, TH17 cells, fueling a long-standing debate in the neuroimmunology field. Here, we demonstrated that mice deficient for IL-17A/F lose their susceptibility to EAE, which correlated with an altered composition of their gut microbiota. However, loss of IL-17A/F in TH cells did not diminish their encephalitogenic capacity. Reconstitution of a wild-type-like intestinal microbiota or reintroduction of IL-17A specifically into the gut epithelium of IL-17A/F-deficient mice reestablished their susceptibility to EAE. Thus, our data demonstrated that IL-17A and IL-17F are not encephalitogenic mediators but rather modulators of intestinal homeostasis that indirectly alter CNS-directed autoimmunity.


Assuntos
Encefalomielite Autoimune Experimental/imunologia , Microbioma Gastrointestinal/imunologia , Interleucina-17/metabolismo , Esclerose Múltipla/imunologia , Transferência Adotiva , Animais , Sistema Nervoso Central/imunologia , Sistema Nervoso Central/patologia , Encefalomielite Autoimune Experimental/microbiologia , Encefalomielite Autoimune Experimental/patologia , Transplante de Microbiota Fecal , Feminino , Humanos , Interleucina-17/genética , Masculino , Camundongos , Camundongos Knockout , Esclerose Múltipla/patologia , Células Th17/imunologia , Células Th17/transplante
7.
Science ; 371(6525): 145-153, 2021 01 08.
Artigo em Inglês | MEDLINE | ID: mdl-33414215

RESUMO

The ability to control autoreactive T cells without inducing systemic immune suppression is the major goal for treatment of autoimmune diseases. The key challenge is the safe and efficient delivery of pharmaceutically well-defined antigens in a noninflammatory context. Here, we show that systemic delivery of nanoparticle-formulated 1 methylpseudouridine-modified messenger RNA (m1Ψ mRNA) coding for disease-related autoantigens results in antigen presentation on splenic CD11c+ antigen-presenting cells in the absence of costimulatory signals. In several mouse models of multiple sclerosis, the disease is suppressed by treatment with such m1Ψ mRNA. The treatment effect is associated with a reduction of effector T cells and the development of regulatory T cell (Treg cell) populations. Notably, these Treg cells execute strong bystander immunosuppression and thus improve disease induced by cognate and noncognate autoantigens.


Assuntos
Efeito Espectador/imunologia , Encefalomielite Autoimune Experimental/terapia , Terapia de Imunossupressão/métodos , Esclerose Múltipla/terapia , Vacinas Sintéticas/uso terapêutico , Animais , Células Apresentadoras de Antígenos , Autoantígenos/genética , Inflamação/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Pseudouridina/análogos & derivados , Pseudouridina/química , RNA Mensageiro/efeitos adversos , RNA Mensageiro/química , RNA Mensageiro/genética , Linfócitos T Reguladores/imunologia , Vacinas Sintéticas/efeitos adversos , Vacinas de mRNA
9.
J Allergy Clin Immunol ; 146(3): 652-666.e11, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32445838

RESUMO

BACKGROUND: Effector functions of IgG Abs are regulated by their Fc N-glycosylation pattern. IgG Fc glycans that lack galactose and terminal sialic acid residues correlate with the severity of inflammatory (auto)immune disorders and have also been linked to protection against viral infection and discussed in the context of vaccine-induced protection. In contrast, sialylated IgG Abs have shown immunosuppressive effects. OBJECTIVE: We sought to investigate IgG glycosylation programming during the germinal center (GC) reaction following immunization of mice with a foreign protein antigen and different adjuvants. METHODS: Mice were analyzed for GC T-cell, B-cell, and plasma cell responses, as well as for antigen-specific serum IgG subclass titers and Fc glycosylation patterns. RESULTS: Different adjuvants induce distinct IgG+ GC B-cell responses with specific transcriptomes and expression levels of the α2,6-sialyltransferase responsible for IgG sialylation that correspond to distinct serum IgG Fc glycosylation patterns. Low IgG Fc sialylation programming in GC B cells was overall highly dependent on the Foxp3- follicular helper T (TFH) cell-inducing cytokine IL-6, here in particular induced by water-in-oil adjuvants and Mycobacterium tuberculosis. Furthermore, low IgG Fc sialylation programming was dependent on adjuvants that induced IL-27 receptor-dependent IFN-γ+ TFH1 cells, IL-6/IL-23-dependent IL-17A+ TFH17 cells, and high ratios of TFH cells to Foxp3+ follicular regulatory T cells. Here, the 2 latter were dependent on M tuberculosis and its cord factor. CONCLUSION: This study's findings regarding adjuvant-dependent GC responses and IgG glycosylation programming may aid in the development of novel vaccination strategies to induce IgG Abs with both high affinity and defined Fc glycosylation patterns in the GC.


Assuntos
Adjuvantes Imunológicos/administração & dosagem , Antígenos/administração & dosagem , Centro Germinativo/imunologia , Imunoglobulina G/imunologia , Compostos de Alúmen/administração & dosagem , Animais , Linfócitos B/efeitos dos fármacos , Linfócitos B/imunologia , Citocinas/imunologia , Feminino , Adjuvante de Freund/administração & dosagem , Glicosilação , Lipopolissacarídeos/administração & dosagem , Camundongos Endogâmicos C57BL , Camundongos Knockout , Óleo Mineral/administração & dosagem , Mycobacterium tuberculosis/imunologia , Ovalbumina/administração & dosagem , Polissorbatos/administração & dosagem , Esqualeno/administração & dosagem , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Vacinação
10.
Front Immunol ; 11: 614509, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33391287

RESUMO

Systemic inflammation is associated with alterations in complex brain functions such as learning and memory. However, diagnostic approaches to functionally assess and quantify inflammation-associated alterations in synaptic plasticity are not well-established. In previous work, we demonstrated that bacterial lipopolysaccharide (LPS)-induced systemic inflammation alters the ability of hippocampal neurons to express synaptic plasticity, i.e., the long-term potentiation (LTP) of excitatory neurotransmission. Here, we tested whether synaptic plasticity induced by repetitive magnetic stimulation (rMS), a non-invasive brain stimulation technique used in clinical practice, is affected by LPS-induced inflammation. Specifically, we explored brain tissue cultures to learn more about the direct effects of LPS on neural tissue, and we tested for the plasticity-restoring effects of the anti-inflammatory cytokine interleukin 10 (IL10). As shown previously, 10 Hz repetitive magnetic stimulation (rMS) of organotypic entorhino-hippocampal tissue cultures induced a robust increase in excitatory neurotransmission onto CA1 pyramidal neurons. Furthermore, LPS-treated tissue cultures did not express rMS-induced synaptic plasticity. Live-cell microscopy in tissue cultures prepared from a novel transgenic reporter mouse line [C57BL/6-Tg(TNFa-eGFP)] confirms that ex vivo LPS administration triggers microglial tumor necrosis factor alpha (TNFα) expression, which is ameliorated in the presence of IL10. Consistent with this observation, IL10 hampers the LPS-induced increase in TNFα, IL6, IL1ß, and IFNγ and restores the ability of neurons to express rMS-induced synaptic plasticity in the presence of LPS. These findings establish organotypic tissue cultures as a suitable model for studying inflammation-induced alterations in synaptic plasticity, thus providing a biological basis for the diagnostic use of transcranial magnetic stimulation in the context of brain inflammation.


Assuntos
Hipocampo/fisiologia , Interleucina-10/farmacologia , Plasticidade Neuronal/fisiologia , Neurônios/fisiologia , Fator de Necrose Tumoral alfa/metabolismo , Animais , Genes Reporter , Hipocampo/metabolismo , Hipocampo/efeitos da radiação , Inflamação/metabolismo , Interferon gama/metabolismo , Interleucina-10/metabolismo , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Lipopolissacarídeos/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Microglia/metabolismo , Plasticidade Neuronal/efeitos dos fármacos , Plasticidade Neuronal/efeitos da radiação , Neurônios/metabolismo , Organoides , Transmissão Sináptica/fisiologia , Transmissão Sináptica/efeitos da radiação , Estimulação Magnética Transcraniana
11.
J Immunol ; 201(11): 3218-3228, 2018 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-30355786

RESUMO

17ß-Estradiol (E2) suppresses the development of experimental autoimmune encephalomyelitis (EAE) through estrogen receptor (ER) α, yet the cellular targets remain elusive. We have used an adoptive transfer model of myelin oligodendrocyte glycoprotein-specific CD4+ T cells from 2D2 TCR transgenic mice. We show that in the recipient mice, ERα expression in bystander CD4+ T cells, rather than in cognate 2D2 T cells, is required for the inhibition of Th17 cell differentiation by E2. Coadministration of estrogen-primed WT, but not ERα-deficient CD4+ T cells, with naive 2D2 T cells lacking ERα inhibited the development of Th17 cell-mediated EAE. Suppression of Th17 cells and protection from EAE were maintained when ERα was deleted in Foxp3+ regulatory T cells. We showed that in vivo PD-L1 blockade alleviated the anti-inflammatory action of E2 and that PD-1 expression on cognate but not bystander T cells was required for the E2-dependent inhibition of Th17 differentiation. In cotransfer experiments, we found that only WT but not PD-1KO 2D2 T cells were amenable to E2-dependent inhibition of Th17 differentiation. These results support the conclusion that the restriction of Th17 cell development by E2-primed bystander CD4+ T cells requires cell-intrinsic PD-1 signaling within cognate T cells rather than induction of regulatory 2D2 T cells through PD-1 engagement. Altogether, our results indicate that pregnancy-level concentrations of estrogen signal in conventional Foxp3neg CD4+ T cells to limit the differentiation of cognate Th17 cells through a trans-acting mechanism of suppression that requires a functional PD-1/PD-L1 regulatory axis.


Assuntos
Efeito Espectador , Sistema Nervoso Central/imunologia , Estrogênios/metabolismo , Linfócitos T Reguladores/imunologia , Células Th17/imunologia , Transferência Adotiva , Animais , Anticorpos Monoclonais/administração & dosagem , Autoimunidade , Antígeno B7-H1/imunologia , Antígenos CD4/metabolismo , Diferenciação Celular , Modelos Animais de Doenças , Receptor alfa de Estrogênio/genética , Feminino , Fatores de Transcrição Forkhead/metabolismo , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Glicoproteína Mielina-Oligodendrócito/imunologia , Receptor de Morte Celular Programada 1/metabolismo , Transdução de Sinais
12.
PLoS One ; 13(2): e0191927, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29408931

RESUMO

In this study we analysed the effects of prophylactic biolistic DNA vaccination with plasmids encoding the encephalitogenic protein myelin oligodendrocyte glycoprotein (MOG) on the severity of a subsequently MOGp35-55-induced EAE and on the underlying immune response. We compared the outcome of vaccination with MOG-encoding plasmids alone or in combination with vectors encoding the regulatory cytokines IL-10 and TGF-ß1, respectively. MOG expression was restricted to skin dendritic cells (DCs) by the use of the DC-specific promoter of the fascin1 gene (pFscn-MOG). For comparison, the strong and ubiquitously active CMV promoter was employed (pCMV-MOG), which allows MOG expression in all transfected cells. Expression of IL-10 and TGF-ß1 was controlled by the CMV promoter to yield maximal synthesis (pCMV-IL10, pCMV-TGFß). Co-application of pFscn-MOG and pCMV-IL10 significantly ameliorated EAE pathology, while vaccination with pCMV-MOG plus pCMV-IL10 did not affect EAE outcome. In contrast, vaccination with either of the two MOG-encoding plasmids in combination with pCMV-TGFß significantly attenuated the clinical EAE symptoms. Mechanistically, we observed diminished infiltration of Th17 and Th1 cells as well as macrophages/DCs into the CNS, which correlated with decreased MOGp35-55-specific production of IL-17 and IFN-Ï« by spleen cells and reduced peptide-specific T cell proliferation. Our findings suggest deletion of or anergy induction in MOG-specific CD4+ T cells by the suppressive vaccination platform employed. MOG expression driven by the DC-specific fascin1 promoter yielded similar inhibitory effects on EAE progression as the ubiquitously active viral CMV promoter, when coapplying pCMV-TGFß. Our finding that pCMV-IL10 promoted tolerogenic effects only, when coapplied with pFscn-MOG, but not pCMV-MOG suggests that IL-10 affected only directly transfected DCs (pFscn-MOG), but not neighbouring DCs that engulfed MOG-containing vesicles derived from transfected keratinocytes (pCMV-MOG). Thus, due to its DC-restricted expression, the fascin1 promoter might be an interesting alternative to ubiquitously expressed promoters for vaccination strategies.


Assuntos
Células Dendríticas/imunologia , Encefalomielite Autoimune Experimental/prevenção & controle , Tolerância Imunológica , Vacinas de DNA/administração & dosagem , Animais , Citometria de Fluxo , Camundongos , Linfócitos T Reguladores/imunologia
13.
EMBO J ; 36(22): 3292-3308, 2017 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-28963396

RESUMO

Microglia are resident macrophages of the central nervous system that contribute to homeostasis and neuroinflammation. Although known to play an important role in brain development, their exact function has not been fully described. Here, we show that in contrast to healthy adult and inflammation-activated cells, neonatal microglia show a unique myelinogenic and neurogenic phenotype. A CD11c+ microglial subset that predominates in primary myelinating areas of the developing brain expresses genes for neuronal and glial survival, migration, and differentiation. These cells are the major source of insulin-like growth factor 1, and its selective depletion from CD11c+ microglia leads to impairment of primary myelination. CD11c-targeted toxin regimens induced a selective transcriptional response in neonates, distinct from adult microglia. CD11c+ microglia are also found in clusters of repopulating microglia after experimental ablation and in neuroinflammation in adult mice, but despite some similarities, they do not recapitulate neonatal microglial characteristics. We therefore identify a unique phenotype of neonatal microglia that deliver signals necessary for myelination and neurogenesis.


Assuntos
Encéfalo/citologia , Encéfalo/embriologia , Microglia/metabolismo , Bainha de Mielina/metabolismo , Neurogênese , Envelhecimento/genética , Animais , Animais Recém-Nascidos , Biomarcadores/metabolismo , Encéfalo/ultraestrutura , Antígeno CD11c/metabolismo , Agregação Celular , Encefalomielite Autoimune Experimental/genética , Encefalomielite Autoimune Experimental/patologia , Feminino , Perfilação da Expressão Gênica , Regulação da Expressão Gênica no Desenvolvimento , Fator de Crescimento Insulin-Like I/metabolismo , Camundongos Endogâmicos C57BL , Placa Neural/metabolismo , Regulação para Cima/genética
15.
Immunity ; 46(6): 943-956, 2017 06 20.
Artigo em Inglês | MEDLINE | ID: mdl-28636961

RESUMO

The central nervous system (CNS) and its meningeal coverings accommodate a diverse myeloid compartment that includes parenchymal microglia and perivascular macrophages, as well as choroid plexus and meningeal macrophages, dendritic cells, and granulocytes. These myeloid populations enjoy an intimate relationship with the CNS, where they play an essential role in both health and disease. Although the importance of these cells is clearly recognized, their exact function in the CNS continues to be explored. Here, we review the subsets of myeloid cells that inhabit the parenchyma, meninges, and choroid plexus and discuss their roles in CNS homeostasis. We also discuss the role of these cells in various neurological pathologies, such as autoimmunity, mechanical injury, neurodegeneration, and infection. We highlight the neuroprotective nature of certain myeloid cells by emphasizing their therapeutic potential for the treatment of neurological conditions.


Assuntos
Doenças Autoimunes/imunologia , Plexo Corióideo/imunologia , Infecções/imunologia , Células Mieloides/fisiologia , Doenças Neurodegenerativas/imunologia , Neuroimunomodulação , Ferimentos e Lesões/imunologia , Animais , Sistema Nervoso Central , Humanos , Meninges/imunologia , Neuroproteção
17.
Cell Rep ; 18(5): 1270-1284, 2017 01 31.
Artigo em Inglês | MEDLINE | ID: mdl-28147280

RESUMO

Arrival of encephalitogenic T cells at inflammatory foci represents a critical step in development of experimental autoimmune encephalomyelitis (EAE), the animal model for multiple sclerosis. EBI2 and its ligand, 7α,25-OHC, direct immune cell localization in secondary lymphoid organs. CH25H and CYP7B1 hydroxylate cholesterol to 7α,25-OHC. During EAE, we found increased expression of CH25H by microglia and CYP7B1 by CNS-infiltrating immune cells elevating the ligand concentration in the CNS. Two critical pro-inflammatory cytokines, interleukin-23 (IL-23) and interleukin-1 beta (IL-1ß), maintained expression of EBI2 in differentiating Th17 cells. In line with this, EBI2 enhanced early migration of encephalitogenic T cells into the CNS in a transfer EAE model. Nonetheless, EBI2 was dispensable in active EAE. Human Th17 cells do also express EBI2, and EBI2 expressing cells are abundant within multiple sclerosis (MS) white matter lesions. These findings implicate EBI2 as a mediator of CNS autoimmunity and describe mechanistically its contribution to the migration of autoreactive T cells into inflamed organs.


Assuntos
Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD4-Positivos/fisiologia , Movimento Celular/fisiologia , Sistema Nervoso Central/metabolismo , Encefalomielite Autoimune Experimental/metabolismo , Esclerose Múltipla/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Animais , Autoimunidade/fisiologia , Sistema Nervoso Central/fisiologia , Família 7 do Citocromo P450/metabolismo , Modelos Animais de Doenças , Encefalomielite Autoimune Experimental/patologia , Feminino , Interleucina-1beta/metabolismo , Interleucina-23/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Esteroide Hidroxilases/metabolismo , Células Th17/metabolismo , Células Th17/fisiologia
18.
Proc Natl Acad Sci U S A ; 114(8): E1480-E1489, 2017 02 21.
Artigo em Inglês | MEDLINE | ID: mdl-28167776

RESUMO

TGF-ß is an anti-inflammatory cytokine whose signaling is negatively controlled by Smad7. Previously, we established a role for Smad7 in the generation of autoreactive T cells; however, the function of Smad7 in dendritic cells (DCs) remains elusive. Here, we demonstrate that DC-specific Smad7 deficiency resulted in elevated expression of the transcription factors Batf3 and IRF8, leading to increased frequencies of CD8+CD103+ DCs in the spleen. Furthermore, Smad7-deficient DCs expressed higher levels of indoleamine 2,3-dioxygenase (IDO), an enzyme associated with tolerance induction. Mice devoid of Smad7 specifically in DCs are resistant to the development of experimental autoimmune encephalomyelitis (EAE) as a result of an increase of protective regulatory T cells (Tregs) and reduction of encephalitogenic effector T cells in the central nervous system. In agreement, inhibition of IDO activity or depletion of Tregs restored disease susceptibility. Intriguingly, when Smad7-deficient DCs also lacked the IFN-γ receptor, the mice regained susceptibility to EAE, demonstrating that IFN-γ signaling in DCs mediates their tolerogenic function. Our data indicate that Smad7 expression governs splenic DC subset differentiation and is critical for the promotion of their efficient function in immunity.


Assuntos
Autoimunidade/fisiologia , Células Dendríticas/metabolismo , Proteína Smad7/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Animais , Fatores de Transcrição de Zíper de Leucina Básica/metabolismo , Linfócitos T CD8-Positivos/metabolismo , Diferenciação Celular/fisiologia , Citocinas/metabolismo , Encefalomielite Autoimune Experimental/metabolismo , Tolerância Imunológica , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Fatores Reguladores de Interferon/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Transdução de Sinais/fisiologia , Baço/metabolismo , Linfócitos T Reguladores/metabolismo
19.
Nat Immunol ; 18(1): 74-85, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27893700

RESUMO

The cellular sources of interleukin 6 (IL-6) that are relevant for differentiation of the TH17 subset of helper T cells remain unclear. Here we used a novel strategy for the conditional deletion of distinct IL-6-producing cell types to show that dendritic cells (DCs) positive for the signaling regulator Sirpα were essential for the generation of pathogenic TH17 cells. Using their IL-6 receptor α-chain (IL-6Rα), Sirpα+ DCs trans-presented IL-6 to T cells during the process of cognate interaction. While ambient IL-6 was sufficient to suppress the induction of expression of the transcription factor Foxp3 in T cells, trans-presentation of IL-6 by DC-bound IL-6Rα (called 'IL-6 cluster signaling' here) was needed to prevent premature induction of interferon-γ (IFN-γ) expression in T cells and to generate pathogenic TH17 cells in vivo. Our findings should guide therapeutic approaches for the treatment of TH17-cell-mediated autoimmune diseases.


Assuntos
Sistema Nervoso Central/imunologia , Células Dendríticas/imunologia , Encefalomielite Autoimune Experimental/imunologia , Subunidade alfa de Receptor de Interleucina-6/genética , Interleucina-6/metabolismo , Células Th17/imunologia , Animais , Autoimunidade , Diferenciação Celular , Células Cultivadas , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/metabolismo , Humanos , Ativação Linfocitária , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Glicoproteína Mielina-Oligodendrócito/imunologia , Fragmentos de Peptídeos/imunologia , Receptores Imunológicos/genética , Receptores Imunológicos/metabolismo
20.
Semin Immunopathol ; 39(2): 153-163, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-27456849

RESUMO

Dendritic cells (DC) are unique hematopoietic cells, linking innate and adaptive immune responses. In particular, they are considered as the most potent antigen presenting cells, governing both T cell immunity and tolerance. In view of their exceptional ability to present antigen and to interact with T cells, DC play distinct roles in shaping T cell development, differentiation and function. The outcome of the DC-T cell interaction is determined by the state of DC maturation, the type of DC subset, the cytokine microenvironment and the tissue location. Both regulatory T cells (Tregs) and DC are indispensable for maintaining central and peripheral tolerance. Over the past decade, accumulating data indicate that DC critically contribute to Treg differentiation and homeostasis.


Assuntos
Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Tolerância Imunológica , Animais , Apresentação de Antígeno/imunologia , Doenças Autoimunes/imunologia , Doenças Autoimunes/metabolismo , Doenças Autoimunes/terapia , Biomarcadores , Comunicação Celular , Diferenciação Celular , Células Dendríticas/classificação , Células Dendríticas/citologia , Homeostase , Humanos , Imunoterapia , Especificidade de Órgãos/imunologia , Fenótipo , Transdução de Sinais , Subpopulações de Linfócitos T
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