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1.
J Immunol ; 205(11): 3001-3010, 2020 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-33127821

RESUMO

The voltage-gated proton channel Hv1 regulates proton fluxes across membranes, thereby influencing pH-dependent processes. Plasmacytoid dendritic cells (pDCs) require a particularly tight regulation of endosomal pH to ensure strong type I IFN secretion exclusively during infection, avoiding autoimmunity. However, whether Hv1 is important for pH control in pDCs is presently unknown. In this study, we show that mouse pDCs require Hv1 to achieve potent type I IFN responses after the recognition of foreign DNA by endosomal TLR9. Genetic disruption of Hvcn1, which encodes Hv1, impaired mouse pDC activation by CpG oligonucleotides in vitro and in vivo, reducing IFN-α secretion and the induction of IFN-stimulated genes. Mechanistically, Hvcn1 deficiency delayed endosomal acidification and enhanced intracellular reactive oxygen species production, consequently limiting protease activity and TLR9 signaling. Our study reveals a critical role of Hv1 during innate immune responses and places this channel as a key modulator of type I IFN production, the hallmark function of pDCs, commending Hv1 as an attractive target for modulating type I IFN-driven autoimmunity.


Assuntos
Células Dendríticas/metabolismo , Canais Iônicos/metabolismo , Receptor Toll-Like 9/metabolismo , Animais , Imunidade Inata/fisiologia , Interferon-alfa/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Oligodesoxirribonucleotídeos/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/fisiologia
2.
J Immunol ; 200(3): 974-982, 2018 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-29298833

RESUMO

Multiple sclerosis (MS) is a T cell-driven inflammatory disease of the CNS. Research on T cell subsets involved in MS pathogenesis has mainly focused on classical CD4+ T cells, especially Th17 cells, as they produce the proinflammatory, MS-associated cytokine IL-17. However, the abundant unconventional mucosal-associated invariant T (MAIT) cells are also able to produce IL-17. MAIT cells are characterized by high CD161 expression and a semi-invariant Vα7.2 TCR, with which they recognize bacterial and yeast Ags derived from the riboflavin (vitamin B2) metabolism. In this study, we characterized MAIT cells from the peripheral blood of MS patients in comparison with healthy individuals with respect to their type-17 differentiation. We found a specific increase of IL-17+ MAIT cells as well as an increased expression of retinoic acid-related orphan receptor (ROR)γt and CCR6 in MAIT cells from MS patients, whereas the expression of T cell activation markers HLA-DR and CD38 was not different. IL-17 production by MAIT cells furthermore correlated with the surface expression level of the IL-7 receptor α-chain (CD127), which was significantly increased on MAIT cells from MS patients in comparison with healthy individuals. In summary, our findings indicate an augmented type-17 differentiation of MAIT cells in MS patients associated with their IL-7 receptor surface expression, implicating a proinflammatory role of these unconventional T cells in MS immunopathology.


Assuntos
Sistema Nervoso Central/patologia , Interleucina-17/biossíntese , Subunidade alfa de Receptor de Interleucina-7/biossíntese , Células T Invariantes Associadas à Mucosa/imunologia , Esclerose Múltipla/patologia , ADP-Ribosil Ciclase 1/metabolismo , Diferenciação Celular/imunologia , Células Cultivadas , Sistema Nervoso Central/imunologia , Antígenos HLA-DR/metabolismo , Humanos , Interferon gama/biossíntese , Ativação Linfocitária/imunologia , Glicoproteínas de Membrana/metabolismo , Células T Invariantes Associadas à Mucosa/metabolismo , Esclerose Múltipla/imunologia , Subfamília B de Receptores Semelhantes a Lectina de Células NK/biossíntese , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/biossíntese , Receptores de Antígenos de Linfócitos T/imunologia , Receptores CCR6/biossíntese , Fator de Transcrição STAT3/metabolismo , Fator de Transcrição STAT5/metabolismo , Transdução de Sinais/imunologia , Proteínas Supressoras de Tumor/metabolismo
3.
Proc Natl Acad Sci U S A ; 114(2): E181-E190, 2017 01 10.
Artigo em Inglês | MEDLINE | ID: mdl-28049829

RESUMO

Pregnancy is one of the strongest inducers of immunological tolerance. Disease activity of many autoimmune diseases including multiple sclerosis (MS) is temporarily suppressed by pregnancy, but little is known about the underlying molecular mechanisms. Here, we investigated the endocrine regulation of conventional and regulatory T cells (Tregs) during reproduction. In vitro, we found the pregnancy hormone progesterone to robustly increase Treg frequencies via promiscuous binding to the glucocorticoid receptor (GR) in T cells. In vivo, T-cell-specific GR deletion in pregnant animals undergoing experimental autoimmune encephalomyelitis (EAE), the animal model of MS, resulted in a reduced Treg increase and a selective loss of pregnancy-induced protection, whereas reproductive success was unaffected. Our data imply that steroid hormones can shift the immunological balance in favor of Tregs via differential engagement of the GR in T cells. This newly defined mechanism confers protection from autoimmunity during pregnancy and represents a potential target for future therapy.


Assuntos
Gravidez/imunologia , Receptores de Glucocorticoides/imunologia , Linfócitos T/imunologia , Animais , Autoimunidade , Encefalomielite Autoimune Experimental/imunologia , Feminino , Tolerância Imunológica , Camundongos Endogâmicos C57BL , Progesterona/imunologia
4.
Brain ; 138(Pt 11): 3263-74, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26359290

RESUMO

Recent association studies have linked numerous genetic variants with an increased risk for multiple sclerosis, although their functional relevance remains largely unknown. Here we investigated phenotypical and functional consequences of a genetic variant in the CD226 gene that, among other autoimmune diseases, predisposes to multiple sclerosis. Phenotypically, effector and regulatory CD4(+) memory T cells of healthy individuals carrying the predisposing CD226 genetic variant showed, in comparison to carriers of the protective variant, reduced surface expression of CD226 and an impaired induction of CD226 after stimulation. This haplotype-dependent reduction in CD226 expression on memory T cells was abrogated in patients with multiple sclerosis, as CD226 expression was comparable to healthy risk haplotype carriers irrespective of genetic variant. Functionally, FOXP3-positive regulatory T cells from healthy carriers of the genetic protective variant showed superior suppressive capacity, which was again abrogated in multiple sclerosis patients. Mimicking the phenotype of human CD226 genetic risk variant carriers, regulatory T cells derived from Cd226-deficient mice showed similarly reduced inhibitory activity, eventually resulting in an exacerbated disease course of experimental autoimmune encephalomyelitis, the animal model of multiple sclerosis. Therefore, by combining human and mouse analyses we show that CD226 exhibits an important role in the activation of regulatory T cells, with its genetically imposed dysregulation impairing regulatory T cell function.


Assuntos
Antígenos de Diferenciação de Linfócitos T/genética , Esclerose Múltipla/genética , RNA Mensageiro/metabolismo , Linfócitos T Reguladores/imunologia , Adulto , Animais , Antígenos de Diferenciação de Linfócitos T/imunologia , Antígenos de Diferenciação de Linfócitos T/metabolismo , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Encefalomielite Autoimune Experimental/genética , Feminino , Fatores de Transcrição Forkhead/metabolismo , Predisposição Genética para Doença , Haplótipos , Heterozigoto , Humanos , Masculino , Camundongos , Camundongos Knockout , Pessoa de Meia-Idade , Esclerose Múltipla/imunologia , Esclerose Múltipla/metabolismo , Fenótipo , Polimorfismo de Nucleotídeo Único , Linfócitos T Reguladores/metabolismo
5.
Eur J Immunol ; 44(10): 3119-28, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25043505

RESUMO

Recent findings indicate a pathogenic involvement of IL-17-producing CD8(+) T cells in multiple sclerosis (MS). IL-17 production has been attributed to a subset of CD8(+) T cells that belong to the mucosal-associated invariant T (MAIT) cell population. Here, we report a reduction of CD8(+) MAIT cells in the blood of MS patients compared with healthy individuals, which significantly correlated with IL-18 serum levels in MS patients. In vitro stimulation of peripheral blood mononuclear cells from healthy individuals and MS patients with IL-18 specifically activated CD8(+) MAIT cells. Moreover, IL-18 together with T-cell receptor stimulation induced, specifically on CD8(+) MAIT cells, an upregulation of the integrin very late antigen-4 that is essential for the infiltration of CD8(+) T cells into the CNS. Notably, we were able to identify CD8(+) MAIT cells in MS brain lesions by immunohistochemistry while they were almost absent in the cerebrospinal fluid (CSF). In summary, our findings indicate that an IL-18-driven activation of CD8(+) MAIT cells contributes to their CNS infiltration in MS, in turn leading to reduced CD8(+) MAIT-cell frequencies in the blood. Therefore, CD8(+) MAIT cells seem to play a role in the innate arm of immunopathology in MS.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Interleucina-18/sangue , Esclerose Múltipla/imunologia , Subpopulações de Linfócitos T/imunologia , Quimiotaxia de Leucócito , Citometria de Fluxo , Humanos , Imuno-Histoquímica , Ativação Linfocitária/imunologia , Esclerose Múltipla/sangue , Esclerose Múltipla/patologia
6.
Sci Adv ; 9(38): eadh1653, 2023 09 22.
Artigo em Inglês | MEDLINE | ID: mdl-37729408

RESUMO

Migratory dendritic cells (migDCs) continuously patrol tissues and are activated by injury and inflammation. Extracellular adenosine triphosphate (ATP) is released by damaged cells or actively secreted during inflammation and increases migDC motility. However, the underlying molecular mechanisms by which ATP accelerates migDC migration is not understood. Here, we show that migDCs can be distinguished from other DC subsets and immune cells by their expression of the voltage-gated calcium channel subunit ß3 (Cavß3; CACNB3), which exclusively facilitates ATP-dependent migration in vitro and during tissue damage in vivo. By contrast, CACNB3 does not regulate lipopolysaccharide-dependent migration. Mechanistically, CACNB3 regulates ATP-dependent inositol 1,4,5-trisphophate receptor-controlled calcium release from the endoplasmic reticulum. This, in turn, is required for ATP-mediated suppression of adhesion molecules, their detachment, and initiation of migDC migration. Thus, Cacnb3-deficient migDCs have an impaired migration after ATP exposure. In summary, we identified CACNB3 as a master regulator of ATP-dependent migDC migration that controls tissue-specific immunological responses during injury and inflammation.


Assuntos
Trifosfato de Adenosina , Canais de Cálcio , Humanos , Transporte Biológico , Inflamação , Células Dendríticas
7.
Med ; 2(3): 296-312.e8, 2021 03 12.
Artigo em Inglês | MEDLINE | ID: mdl-33748804

RESUMO

BACKGROUND: Multiple sclerosis (MS), an autoimmune disease of the central nervous system (CNS), can be suppressed in its early stages but eventually becomes clinically progressive and unresponsive to therapy. Here, we investigate whether the therapeutic resistance of progressive MS can be attributed to chronic immune cell accumulation behind the blood-brain barrier (BBB). METHODS: We systematically track CNS-homing immune cells in the peripheral blood of 31 MS patients and 31 matched healthy individuals in an integrated analysis of 497,705 single-cell transcriptomes and 355,433 surface protein profiles from 71 samples. Through spatial RNA sequencing, we localize these cells in post mortem brain tissue of 6 progressive MS patients contrasted against 4 control brains (20 samples, 85,000 spot transcriptomes). FINDINGS: We identify a specific pathogenic CD161+/lymphotoxin beta (LTB)+ T cell population that resides in brains of progressive MS patients. Intriguingly, our data suggest that the colonization of the CNS by these T cells may begin earlier in the disease course, as they can be mobilized to the blood by usage of the integrin-blocking antibody natalizumab in relapsing-remitting MS patients. CONCLUSIONS: As a consequence, we lay the groundwork for a therapeutic strategy to deplete CNS-homing T cells before they can fuel treatment-resistant progression. FUNDING: This study was supported by funding from the University Medical Center Hamburg-Eppendorf, the Stifterverband für die Deutsche Wissenschaft, the OAK Foundation, Medical Research Council UK, and Wellcome.


Assuntos
Esclerose Múltipla Crônica Progressiva , Esclerose Múltipla Recidivante-Remitente , Esclerose Múltipla , Sistema Nervoso Central/patologia , Humanos , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla Crônica Progressiva/tratamento farmacológico , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Natalizumab/uso terapêutico , Linfócitos T/patologia
8.
Sci Immunol ; 1(3): eaaf8665, 2016 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-28783680

RESUMO

Skin-migratory dendritic cells (migDCs) are pivotal antigen-presenting cells that continuously transport antigens to draining lymph nodes and regulate immune responses. However, identification of migDCs is complicated by the lack of distinguishing markers, and it remains unclear which molecules determine their migratory capacity during inflammation. We show that, in the skin, the neuronal plasticity molecule activity-regulated cytoskeleton-associated protein/activity-regulated gene 3.1 (Arc/Arg3.1) was strictly confined to migDCs. Mechanistically, Arc/Arg3.1 was required for accelerated DC migration during inflammation because it regulated actin dynamics through nonmuscle myosin II. Accordingly, Arc/Arg3.1-dependent DC migration was critical for mounting T cell responses in experimental autoimmune encephalomyelitis and allergic contact dermatitis. Thus, Arc/Arg3.1 was restricted to migDCs in the skin and drove fast DC migration by exclusively coordinating cytoskeletal changes in response to inflammatory challenges. These findings commend Arc/Arg3.1 as a universal switch in migDCs that may be exploited to selectively modify immune responses.

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