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1.
Nat Immunol ; 22(3): 322-335, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33531712

RESUMO

Immune system dysfunction is paramount in coronavirus disease 2019 (COVID-19) severity and fatality rate. Mucosal-associated invariant T (MAIT) cells are innate-like T cells involved in mucosal immunity and protection against viral infections. Here, we studied the immune cell landscape, with emphasis on MAIT cells, in cohorts totaling 208 patients with various stages of disease. MAIT cell frequency is strongly reduced in blood. They display a strong activated and cytotoxic phenotype that is more pronounced in lungs. Blood MAIT cell alterations positively correlate with the activation of other innate cells, proinflammatory cytokines, notably interleukin (IL)-18, and with the severity and mortality of severe acute respiratory syndrome coronavirus 2 infection. We also identified a monocyte/macrophage interferon (IFN)-α-IL-18 cytokine shift and the ability of infected macrophages to induce the cytotoxicity of MAIT cells in an MR1-dependent manner. Together, our results suggest that altered MAIT cell functions due to IFN-α-IL-18 imbalance contribute to disease severity, and their therapeutic manipulation may prevent deleterious inflammation in COVID-19 aggravation.


Assuntos
COVID-19/imunologia , Interferon-alfa/imunologia , Interleucina-18/imunologia , Macrófagos/imunologia , Monócitos/imunologia , Células T Invariantes Associadas à Mucosa/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Lavagem Broncoalveolar , Estudos de Casos e Controles , Chlorocebus aethiops , Estudos de Coortes , Feminino , França , Humanos , Imunofenotipagem , Interleucina-10/imunologia , Interleucina-15/imunologia , Interleucina-1beta/imunologia , Interleucina-6/imunologia , Interleucina-8/imunologia , Masculino , Pessoa de Meia-Idade , RNA-Seq , SARS-CoV-2 , Índice de Gravidade de Doença , Análise de Célula Única , Células Vero , Adulto Jovem
2.
Immunity ; 56(9): 1980-1982, 2023 09 12.
Artigo em Inglês | MEDLINE | ID: mdl-37703826

RESUMO

Lymph nodes can be shared among several organs, notably in the gastrointestinal system. In this issue of Immunity, Brown et al. describe how pancreatic immunity is shaped by the mixing of different migratory dendritic cells issued from co-drainage from liver, pancreas, and duodenum.


Assuntos
Trato Gastrointestinal , Pâncreas , Fígado , Linfonodos
3.
Nat Immunol ; 19(9): 1035, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29880894

RESUMO

In the version of this Article originally published, the asterisks indicating statistical significance were missing from Supplementary Figure 6; the file with the correct figure is now available.

4.
Nat Immunol ; 18(12): 1321-1331, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28991267

RESUMO

Type 1 diabetes (T1D) is an autoimmune disease that results from the destruction of pancreatic ß-cells by the immune system that involves innate and adaptive immune cells. Mucosal-associated invariant T cells (MAIT cells) are innate-like T-cells that recognize derivatives of precursors of bacterial riboflavin presented by the major histocompatibility complex (MHC) class I-related molecule MR1. Since T1D is associated with modification of the gut microbiota, we investigated MAIT cells in this pathology. In patients with T1D and mice of the non-obese diabetic (NOD) strain, we detected alterations in MAIT cells, including increased production of granzyme B, which occurred before the onset of diabetes. Analysis of NOD mice that were deficient in MR1, and therefore lacked MAIT cells, revealed a loss of gut integrity and increased anti-islet responses associated with exacerbated diabetes. Together our data highlight the role of MAIT cells in the maintenance of gut integrity and the control of anti-islet autoimmune responses. Monitoring of MAIT cells might represent a new biomarker of T1D, while manipulation of these cells might open new therapeutic strategies.


Assuntos
Diabetes Mellitus Tipo 1/imunologia , Antígenos de Histocompatibilidade Classe I/análise , Mucosa Intestinal/imunologia , Antígenos de Histocompatibilidade Menor/análise , Células T Invariantes Associadas à Mucosa/imunologia , Pâncreas/imunologia , Animais , Células Cultivadas , Microbioma Gastrointestinal/imunologia , Granzimas/biossíntese , Humanos , Células Secretoras de Insulina/imunologia , Mucosa Intestinal/citologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , Pâncreas/citologia
6.
Gut ; 71(2): 296-308, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-33593807

RESUMO

OBJECTIVE: Type 1 diabetes (T1D) is an autoimmune disease caused by the destruction of pancreatic ß-cells producing insulin. Both T1D patients and animal models exhibit gut microbiota and mucosa alterations, although the exact cause for these remains poorly understood. We investigated the production of key cytokines controlling gut integrity, the abundance of segmented filamentous bacteria (SFB) involved in the production of these cytokines, and the respective role of autoimmune inflammation and hyperglycaemia. DESIGN: We used several mouse models of autoimmune T1D as well as mice rendered hyperglycaemic without inflammation to study gut mucosa and microbiota dysbiosis. We analysed cytokine expression in immune cells, epithelial cell function, SFB abundance and microbiota composition by 16S sequencing. We assessed the role of anti-tumour necrosis factor α on gut mucosa inflammation and T1D onset. RESULTS: We show in models of autoimmune T1D a conserved loss of interleukin (IL)-17A, IL-22 and IL-23A in gut mucosa. Intestinal epithelial cell function was altered and gut integrity was impaired. These defects were associated with dysbiosis including progressive loss of SFB. Transfer of diabetogenic T-cells recapitulated these gut alterations, whereas induction of hyperglycaemia with no inflammation failed to do so. Moreover, anti-inflammatory treatment restored gut mucosa and immune cell function and dampened diabetes incidence. CONCLUSION: Our results demonstrate that gut mucosa alterations and dysbiosis in T1D are primarily linked to inflammation rather than hyperglycaemia. Anti-inflammatory treatment preserves gut homeostasis and protective commensal flora reducing T1D incidence.


Assuntos
Bactérias/isolamento & purificação , Diabetes Mellitus Tipo 1/complicações , Disbiose/etiologia , Microbioma Gastrointestinal , Mucosa Intestinal/microbiologia , Mucosa Intestinal/patologia , Animais , Citocinas/metabolismo , Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Tipo 1/microbiologia , Modelos Animais de Doenças , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Hiperglicemia/etiologia , Inflamação/etiologia , Mucosa Intestinal/metabolismo , Camundongos
7.
Diabetologia ; 64(10): 2306-2321, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34350463

RESUMO

AIMS/HYPOTHESIS: Mucosal-associated invariant T (MAIT) cells are innate-like T lymphocytes expressing an αß T cell antigen receptor that recognises the MHC-related 1 molecule. MAIT cells are altered in children at risk for and with type 1 diabetes, and mouse model studies have shown MAIT cell involvement in type 1 diabetes development. Since several studies support heterogeneity in type 1 diabetes physiopathology according to the age of individuals, we investigated whether MAIT cells were altered in adults with type 1 diabetes. METHODS: MAIT cell frequency, phenotype and function were analysed by flow cytometry, using fresh peripheral blood from 21 adults with recent-onset type 1 diabetes (2-14 days after disease onset) and 47 adults with long-term disease (>2 years after diagnosis) compared with 55 healthy blood donors. We also separately analysed 17 women with long-term type 1 diabetes and an associated autoimmune disease, compared with 30 healthy women and 27 women with long-term type 1 diabetes. RESULTS: MAIT cells from adults with recent-onset type 1 diabetes, compared with healthy adult donors, harboured a strongly activated phenotype indicated by an elevated CD25+ MAIT cell frequency. In adults with long-term type 1 diabetes, MAIT cells displayed an activated and exhausted phenotype characterised by high CD25 and programmed cell death 1 (PD1) expression and a decreased production of proinflammatory cytokines, IL-2, IFN-γ and TNF-α. Even though MAIT cells from these patients showed upregulated IL-17 and IL-4 production, the polyfunctionality of MAIT cells was decreased (median 4.8 vs 13.14% of MAIT cells, p < 0.001) and the frequency of MAIT cells producing none of the effector molecules analysed increased (median 34.40 vs 19.30% of MAIT cells, p < 0.01). Several MAIT cell variables correlated with HbA1c level and more particularly in patients with recent-onset type 1 diabetes. In women with long-term type 1 diabetes, MAIT cell alterations were more pronounced in those with an associated autoimmune disease than in those without another autoimmune disease. In women with long-term type 1 diabetes and an associated autoimmune disease, there was an increase in CD69 expression and a decrease in the survival B-cell lymphoma 2 (BCL-2) (p < 0.05) and CD127 (IL-7R) (p < 0.01) marker expression compared with women without a concomitant autoimmune disorder. Concerning effector molecules, TNF-α and granzyme B production by MAIT cells was decreased. CONCLUSIONS/INTERPRETATION: Alterations in MAIT cell frequency, phenotype and function were more pronounced in adults with long-term type 1 diabetes compared with adults with recent-onset type 1 diabetes. There were several correlations between MAIT cell variables and clinical characteristics. Moreover, the presence of another autoimmune disease in women with long-term type 1 diabetes further exacerbated MAIT cell alterations. Our results suggest that MAIT cell alterations in adults with type 1 diabetes could be associated with two aspects of the disease: impaired glucose homeostasis; and autoimmunity.


Assuntos
Diabetes Mellitus Tipo 1/patologia , Células T Invariantes Associadas à Mucosa/patologia , Adulto , Idoso , Antígenos CD , Antígenos de Diferenciação de Linfócitos T , Biomarcadores/metabolismo , Doadores de Sangue , Citocinas/metabolismo , Diabetes Mellitus Tipo 1/metabolismo , Feminino , Citometria de Fluxo , Humanos , Subunidade alfa de Receptor de Interleucina-2/metabolismo , Lectinas Tipo C , Masculino , Pessoa de Meia-Idade , Células T Invariantes Associadas à Mucosa/metabolismo , Fenótipo , Receptor de Morte Celular Programada 1/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2 , Adulto Jovem
8.
FASEB J ; : fj201800052RR, 2018 Apr 27.
Artigo em Inglês | MEDLINE | ID: mdl-29957059

RESUMO

The disruption of systemic immune homeostasis is a key mediator in the progression of cardiometabolic diseases (CMDs). We aimed to extend knowledge regarding the clinical relevance of CMD-associated variation of circulating mucosal-associated invariant T (MAIT) cell abundance and to explore underlying cellular mechanisms. We analyzed cross-sectional data from 439 participants of the Metagenomics in Cardiometabolic Diseases (MetaCardis) study, stratified into 6 groups: healthy control subjects and patients with metabolic syndrome (MS), obesity, type 2 diabetes mellitus (T2DM), and coronary artery disease (CAD) without, or with congestive heart failure (CAD-CHF). Blood MAIT cell frequency was significantly decreased in all CMD groups, including early (MS) and later (CAD and CAD-CHF) stages of disease progression. Reduced MAIT cell abundance was associated with increased glycosylated hemoglobin, inflammation markers, and deterioration of cardiac function. Glucose dose dependently promoted MAIT cell apoptosis in vitro, independently of anti-CD3 and cytokine-mediated activation. This outcome suggests the prominence of metabolic over an antigenic or cytokine-rich environment to promote MAIT cell reduction in patients with CMD. In summary, all stages of CMDs are characterized by reduced circulating MAIT cells. Chronically elevated blood glucose levels could contribute to this decline. These data extend the pathologic relevance of MAIT cell loss and suggest that MAIT cell abundance may serve as an indicator of cardiometabolic health.-Touch, S., Assmann, K. E., Aron-Wisnewsky, J., Marquet, F., Rouault, C., Fradet, M., Mosbah, H., MetaCardis Consortium, Isnard, R., Helft, G., Lehuen, A., Poitou, C., Clément, K., André, S. Mucosal-associated invariant T (MAIT) cells are depleted and prone to apoptosis in cardiometabolic disorders.

9.
Immunol Cell Biol ; 96(6): 618-629, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29405379

RESUMO

Autoimmune and inflammatory diseases have complex etiologies not fully understood. Both innate and adaptive immune cells are involved in the pathogenesis of these diseases. Mucosal-associated invariant T (MAIT) cells express an invariant TCRα chain (Vα7.2-Jα33 in humans and Vα19-Jα33 in mice) and recognize the conserved MHC-I-related molecule MR1 presenting bacterial metabolites derived from the synthesis of vitamin B. MAIT cells harbor tissue homing properties and produce inflammatory cytokines, suggesting that MAIT cells may play a key role in autoimmune and inflammatory diseases. In this review, we described the current knowledge on MAIT cells in these pathologies, based on patients analyses as well as mouse models. While most of the studies support a deleterious role of MAIT cells in tissue inflammation and destruction, a few reports suggest a protective role of MAIT cells. MAIT cells could represent a new biomarker of disease progression, and a better knowledge of their function might open new avenues for therapeutic strategies based on their manipulation.


Assuntos
Doenças Autoimunes/imunologia , Inflamação/imunologia , Células T Invariantes Associadas à Mucosa/imunologia , Animais , Humanos , Doenças do Sistema Imunitário/imunologia
11.
Immunity ; 30(2): 289-99, 2009 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-19217323

RESUMO

Invariant natural killer T (iNKT) cells promote immune responses to various pathogens, but exactly how iNKT cells control antiviral responses is unclear. Here, we showed that iNKT cells induced tissue-specific antiviral effects in mice infected by lymphocytic choriomeningitis virus (LCMV). Indeed, iNKT cells inhibited viral replication in the pancreas and liver but not in the spleen. In the pancreas, iNKT cells expressed the OX40 molecule and promoted type I interferon (IFN) production by plasmacytoid dendritic cells (pDCs) through OX40-OX40 ligand interaction. Subsequently, this iNKT cell-pDC cooperation attenuated the antiviral adaptive immune response in the pancreas but not in the spleen. The dampening of pancreatic anti-LCMV CD8(+) T cell response prevented tissue damage in transgenic mice expressing LCMV protein in islet beta cells. Thus, this study identifies pDCs as an essential partner of iNKT cells for mounting an efficient, nondeleterious antiviral response in peripheral tissue.


Assuntos
Células Dendríticas/imunologia , Coriomeningite Linfocítica/imunologia , Coriomeningite Linfocítica/virologia , Vírus da Coriomeningite Linfocítica/imunologia , Células T Matadoras Naturais/imunologia , Receptores OX40/imunologia , Animais , Linfócitos T CD8-Positivos/imunologia , Diabetes Mellitus/etiologia , Diabetes Mellitus/imunologia , Diabetes Mellitus/virologia , Fígado/imunologia , Fígado/virologia , Coriomeningite Linfocítica/complicações , Camundongos , Ligante OX40/imunologia , Especificidade de Órgãos/imunologia , Pâncreas/imunologia , Pâncreas/virologia , Transdução de Sinais/imunologia , Baço/imunologia , Baço/virologia , Replicação Viral
12.
Eur J Immunol ; 46(9): 2162-74, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27338553

RESUMO

Invariant NKT (iNKT) cells differentiate in the thymus into three distinct lineages defined by their cytokine and transcription factor expression. Signaling lymphocyte activation molecule (SLAM)-associated protein (SAP) is essential for early stages of iNKT cell development, but its role during terminal differentiation of iNKT1, iNKT2, or iNKT17 cells remains unclear. Taking advantage of SAP-deficient mice expressing a Vα14-Jα18 TCRα transgene, we found that SAP is critical not only for IL-4 production but also for the terminal differentiation of IL-4-producing iNKT2 cells. Furthermore, without SAP, the IL-17 producing subset is expanded, while IFN-γ-producing iNKT1 differentiation is only moderately compromised. Lack of SAP reduced the expression of the transcription factors GATA-3 and promyelocytic leukemia zinc finger, but enhanced the levels of retinoic acid receptor-related orphan receptor γt. In the absence of SAP, lineage commitment was actually shifted toward the emergence of iNKT17 over iNKT2 cells. Collectively, our data unveil a new critical regulatory function for SAP in thymic iNKT cell fate decisions.


Assuntos
Diferenciação Celular/imunologia , Células T Matadoras Naturais/citologia , Células T Matadoras Naturais/metabolismo , Proteína Associada à Molécula de Sinalização da Ativação Linfocitária/metabolismo , Subpopulações de Linfócitos T/citologia , Subpopulações de Linfócitos T/metabolismo , Animais , Biomarcadores , Células Cultivadas , Imunofenotipagem , Interleucina-17/biossíntese , Interleucina-4/biossíntese , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/metabolismo , Fenótipo , Proteína Associada à Molécula de Sinalização da Ativação Linfocitária/deficiência , Proteína Associada à Molécula de Sinalização da Ativação Linfocitária/genética
13.
Am J Physiol Gastrointest Liver Physiol ; 311(2): G313-23, 2016 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-27340126

RESUMO

The IL-33/ST2 axis plays a protective role in T-cell-mediated hepatitis, but little is known about the functional impact of endogenous IL-33 on liver immunopathology. We used IL-33-deficient mice to investigate the functional effect of endogenous IL-33 in concanavalin A (Con A)-hepatitis. IL-33(-/-) mice displayed more severe Con A liver injury than wild-type (WT) mice, consistent with a hepatoprotective effect of IL-33. The more severe hepatic injury in IL-33(-/-) mice was associated with significantly higher levels of TNF-α and IL-1ß and a larger number of NK cells infiltrating the liver. The expression of Th2 cytokines (IL-4, IL-10) and IL-17 was not significantly varied between WT and IL-33(-/-) mice following Con A-hepatitis. The percentage of CD25(+) NK cells was significantly higher in the livers of IL-33(-/-) mice than in WT mice in association with upregulated expression of CXCR3 in the liver. Regulatory T cells (Treg cells) strongly infiltrated the liver in both WT and IL-33(-/-) mice, but Con A treatment increased their membrane expression of ST2 and CD25 only in WT mice. In vitro, IL-33 had a significant survival effect, increasing the total number of splenocytes, including B cells, CD4(+) and CD8(+) T cells, and the frequency of ST2(+) Treg cells. In conclusion, IL-33 acts as a potent immune modulator protecting the liver through activation of ST2(+) Treg cells and control of NK cells.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/imunologia , Hepatite/imunologia , Proteína 1 Semelhante a Receptor de Interleucina-1/imunologia , Interleucina-33/deficiência , Células Matadoras Naturais/imunologia , Fígado/inervação , Ativação Linfocitária , Linfócitos T Reguladores/imunologia , Animais , Células Cultivadas , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/patologia , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Quimiotaxia de Leucócito , Concanavalina A , Citocinas/imunologia , Citocinas/metabolismo , Modelos Animais de Doenças , Predisposição Genética para Doença , Hepatite/metabolismo , Hepatite/patologia , Hepatite/prevenção & controle , Mediadores da Inflamação/imunologia , Mediadores da Inflamação/metabolismo , Proteína 1 Semelhante a Receptor de Interleucina-1/metabolismo , Interleucina-33/genética , Células Matadoras Naturais/metabolismo , Fígado/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fenótipo , Transdução de Sinais , Linfócitos T Reguladores/metabolismo
14.
Eur J Immunol ; 44(5): 1454-66, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24481989

RESUMO

Invariant NKT (iNKT)-cell stimulation with exogenous specific ligands prevents the development of type 1 diabetes (T1D) in NOD mice. Studies based on anti-islet T-cell transfer showed that iNKT cells prevent the differentiation of these T cells into effector T cells in the pancreatic lymph nodes (PLNs). We hypothesize that this defective priming could be explained by the ability of iNKT cells to induce tolerogenic dendritic cells (DCs) in the PLNs. We evaluated the effect of iNKT-cell stimulation on T1D development by transferring naïve diabetogenic BDC2.5 T cells into proinsulin 2(-/-) NOD mice treated with a long-lasting α-galactosylceramide regimen. In this context, iNKT cells induce the conversion of BDC2.5 T cells into Foxp3(+) Treg cells in the PLNs accumulating in the pancreatic islets. Furthermore, tolerogenic plasmacytoid DCs (pDCs) characterized by low MHC class II molecule expression and TGF-ß production are critical in the PLNs for the recruitment of Treg cells into the pancreatic islets by inducing CXCR3 expression. Accordingly, pDC depletion in α-galactosylceramide-treated proinsulin 2(-/-) NOD mice abrogates the protection against T1D. These findings reveal that upon repetitive iNKT-cell stimulation, pDCs are critical for the recruitment of Treg cells in the pancreatic islets and the prevention of T1D development.


Assuntos
Células Dendríticas/imunologia , Diabetes Mellitus Tipo 1/imunologia , Ilhotas Pancreáticas/imunologia , Células T Matadoras Naturais/imunologia , Plasmócitos/imunologia , Linfócitos T Reguladores/imunologia , Animais , Células Dendríticas/patologia , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/patologia , Diabetes Mellitus Tipo 1/prevenção & controle , Ilhotas Pancreáticas/patologia , Linfonodos/imunologia , Linfonodos/patologia , Camundongos , Camundongos Endogâmicos NOD , Camundongos Knockout , Células T Matadoras Naturais/patologia , Plasmócitos/patologia , Proinsulina/genética , Proinsulina/imunologia , Linfócitos T Reguladores/patologia
15.
Curr Top Microbiol Immunol ; 382: 221-35, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25116102

RESUMO

Immunoglobulin A (IgA) is the most abundantly produced antibody isotype in mammals. The primary function of IgA is to maintain homeostasis at mucosal surfaces and play a role in immune protection. IgA functions mainly through interaction with multiple receptors including IgA Fc receptor I (FcαRI), transferrin receptor 1 (CD71), asialoglycoprotein receptor (ASGPR), Fcα/µR, FcRL4, and DC-SIGN/SIGNR1. In this review we discuss recent data demonstrating anti-inflammatory functions of IgA through two receptors, the FcαRI and DC-SIGN/SIGNR1 interactions in the regulation of immunity. Serum monomeric IgA is able to mediate an inhibitory signal following the interaction with FcαRI. It results in partial phosphorylation of its FcRγ-ITAM and the recruitment of the tyrosine phosphatase SHP-1, which induces cell inhibition following the formation of intracellular clusters named inhibisomes. In contrast, cross-linking of FcαRI by multimeric ligands induces a full phosphorylation of the FcRγ-ITAM leading to the recruitment of the tyrosine kinase Syk and cell activation. In addition, secretory IgA can mediate a potent anti-inflammatory function following the sugar-dependent interaction with SIGNR1 on dendritic cells which induces an immune tolerance via regulatory T cell expansion. Overall, the anti-inflammatory effect of serum and secretory IgA plays a crucial role in the physiology and in the prevention of tissue damage in multiple autoimmune and inflammatory diseases.


Assuntos
Imunoglobulina A/fisiologia , Inflamação/prevenção & controle , Receptores Fc/fisiologia , Animais , Moléculas de Adesão Celular/fisiologia , Humanos , Imunoglobulina A/química , Imunoglobulina A Secretora/fisiologia , Lectinas Tipo C/fisiologia , Receptores de Superfície Celular/fisiologia , Receptores Fc/química
16.
J Immunol ; 190(7): 3299-308, 2013 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-23427253

RESUMO

Invariant NKT (iNKT) cells play key roles in host defense by recognizing lipid Ags presented by CD1d. iNKT cells are activated by bacterial-derived lipids and are also strongly autoreactive toward self-lipids. iNKT cell responsiveness must be regulated to maintain effective host defense while preventing uncontrolled stimulation and potential autoimmunity. CD1d-expressing thymocytes support iNKT cell development, but thymocyte-restricted expression of CD1d gives rise to Ag hyperresponsive iNKT cells. We hypothesized that iNKT cells require functional education by CD1d(+) cells other than thymocytes to set their correct responsiveness. In mice that expressed CD1d only on thymocytes, hyperresponsive iNKT cells in the periphery expressed significantly reduced levels of tyrosine phosphatase SHP-1, a negative regulator of TCR signaling. Accordingly, heterozygous SHP-1 mutant mice displaying reduced SHP-1 expression developed a comparable population of Ag hyperresponsive iNKT cells. Restoring nonthymocyte CD1d expression in transgenic mice normalized SHP-1 expression and iNKT cell reactivity. Radiation chimeras revealed that CD1d(+) dendritic cells supported iNKT cell upregulation of SHP-1 and decreased responsiveness after thymic emigration. Hence, dendritic cells functionally educate iNKT cells by tuning SHP-1 expression to limit reactivity.


Assuntos
Células Dendríticas/metabolismo , Células T Matadoras Naturais/metabolismo , Proteína Tirosina Fosfatase não Receptora Tipo 6/metabolismo , Animais , Antígenos CD1d/genética , Antígenos CD1d/metabolismo , Análise por Conglomerados , Células Dendríticas/imunologia , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Impressão Genômica , Humanos , Hipersensibilidade/genética , Hipersensibilidade/imunologia , Camundongos , Camundongos Knockout , Células T Matadoras Naturais/imunologia , Proteína Tirosina Fosfatase não Receptora Tipo 6/genética , Timo/imunologia , Timo/metabolismo
17.
J Immunol ; 191(5): 2335-43, 2013 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-23926325

RESUMO

IgA plays ambivalent roles in the immune system. The balance between inhibitory and activating responses relies on the multimerization status of IgA and interaction with their cognate receptors. In mucosal sites, secretory IgA (SIgA) protects the host through immune-exclusion mechanisms, but its function in the bloodstream remains unknown. Using bone marrow-derived dendritic cells, we found that both human and mouse SIgA induce tolerogenic dendritic cells (DCs) following binding to specific ICAM-3 grabbing nonintegrin receptor 1. This interaction was dependent on Ca(2+) and mannose residues. SIgA-primed DCs (SIgA-DCs) are resistant to TLR-dependent maturation. Although SIgA-DCs fail to induce efficient proliferation and Th1 differentiation of naive responder T cells, they generate the expansion of regulatory T cells through IL-10 production. SIgA-DCs are highly potent in inhibiting autoimmune responses in mouse models of type 1 diabetes and multiple sclerosis. This discovery may offer new insights about mucosal-derived DC immunoregulation through SIgA opening new therapeutic approaches to autoimmune diseases.


Assuntos
Autoimunidade/imunologia , Moléculas de Adesão Celular/imunologia , Células Dendríticas/imunologia , Imunoglobulina A Secretora/imunologia , Lectinas Tipo C/imunologia , Receptores de Superfície Celular/imunologia , Animais , Células da Medula Óssea/imunologia , Diferenciação Celular/imunologia , Células Dendríticas/citologia , Citometria de Fluxo , Técnicas de Silenciamento de Genes , Humanos , Tolerância Imunológica/imunologia , Camundongos , Camundongos Endogâmicos C57BL
18.
J Immunol ; 188(7): 3138-49, 2012 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-22371394

RESUMO

Type 1 diabetes (T1D) is a chronic autoimmune disease that results from T cell-mediated destruction of pancreatic ß cells. CD1d-restricted NKT lymphocytes have the ability to regulate immunity, including autoimmunity. We previously demonstrated that CD1d-restricted type II NKT cells, which carry diverse TCRs, prevented T1D in the NOD mouse model for the human disease. In this study, we show that CD4(+) 24αß type II NKT cells, but not CD4/CD8 double-negative NKT cells, were sufficient to downregulate diabetogenic CD4(+) BDC2.5 NOD T cells in adoptive transfer experiments. CD4(+) 24αß NKT cells exhibited a memory phenotype including high ICOS expression, increased cytokine production, and limited display of NK cell markers, compared with double-negative 24αß NKT cells. Blocking of ICOS or the programmed death-1/programmed death ligand 1 pathway was shown to abolish the regulation that occurred in the pancreas draining lymph nodes. To our knowledge, these results provide for the first time cellular and molecular information on how type II CD1d-restricted NKT cells regulate T1D.


Assuntos
Apoptose/imunologia , Diabetes Mellitus Tipo 1/imunologia , Células T Matadoras Naturais/imunologia , Subpopulações de Linfócitos T/imunologia , Transferência Adotiva , Animais , Antígenos CD1d/imunologia , Antígeno B7-H1/fisiologia , Linfócitos T CD4-Positivos/classificação , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/transplante , Diabetes Mellitus Tipo 1/prevenção & controle , Modelos Animais de Doenças , Memória Imunológica , Proteína Coestimuladora de Linfócitos T Induzíveis/fisiologia , Linfonodos/imunologia , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Camundongos Transgênicos , Células T Matadoras Naturais/classificação , Células T Matadoras Naturais/transplante , Pâncreas/imunologia , Pancreatite/prevenção & controle , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos de Linfócitos T/imunologia , Organismos Livres de Patógenos Específicos , Subpopulações de Linfócitos T/transplante , Linfócitos T Reguladores/imunologia
19.
J Immunol ; 189(6): 3007-17, 2012 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-22875802

RESUMO

Recognition of endogenous lipid Ag(s) on CD1d is required for the development of invariant NKT (iNKT) cells. Isoglobotrihexosylceramide (iGb3) has been implicated as this endogenous selecting ligand and recently suggested to control overstimulation and deletion of iNKT cells in α-galactosidase A-deficient (αGalA(-/-)) mice (human Fabry disease), which accumulate isoglobosides and globosides. However, the presence and function of iGb3 in murine thymus remained controversial. In this study, we generate a globotrihexosylceramide (Gb3)-synthase-deficient (Gb3S(-/-)) mouse and show that in thymi of αGalA(-/-)/Gb3S(-/-) double-knockout mice, which store isoglobosides but no globosides, minute amounts of iGb3 can be detected by HPLC. Furthermore, we demonstrate that iGb3 deficiency does not only fail to impact selection of iNKT cells, in terms of frequency and absolute numbers, but also does not alter the distribution of the TCR CDR 3 of iNKT cells. Analyzing multiple gene-targeted mouse strains, we demonstrate that globoside, rather than iGb3, storage is the major cause for reduced iNKT cell frequencies and defective Ag presentation in αGalA(-/-) mice. Finally, we show that correction of globoside storage in αGalA(-/-) mice by crossing them with Gb3S(-/-) normalizes iNKT cell frequencies and dendritic cell (DC) function. We conclude that, although detectable in murine thymus in αGalA(-/-)/Gb3S(-/-) mice, iGb3 does not influence either the development of iNKT cells or their interaction with peripheral DCs. Moreover, in αGalA(-/-) mice, it is the Gb3 storage that is responsible for the decreased iNKT cell numbers and impeded Ag presentation on DCs.


Assuntos
Diferenciação Celular/imunologia , Células Dendríticas/imunologia , Globosídeos/fisiologia , Células T Matadoras Naturais/imunologia , Triexosilceramidas , Animais , Sequência de Carboidratos , Células Dendríticas/enzimologia , Células Dendríticas/metabolismo , Globosídeos/deficiência , Fígado/citologia , Fígado/enzimologia , Fígado/metabolismo , Camundongos , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Dados de Sequência Molecular , Células T Matadoras Naturais/enzimologia , Células T Matadoras Naturais/metabolismo , Baço/citologia , Baço/enzimologia , Baço/metabolismo , Timo/citologia , Timo/enzimologia , Timo/metabolismo , Triexosilceramidas/deficiência , Triexosilceramidas/fisiologia , alfa-Galactosidase/genética , alfa-Galactosidase/fisiologia
20.
Cell Mol Life Sci ; 70(2): 239-55, 2013 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-22766971

RESUMO

Type 1 diabetes is an autoimmune disease characterized by the destruction of insulin-producing pancreatic ß-cells. Even though extensive scientific research has yielded important insights into the immune mechanisms involved in pancreatic ß-cell destruction, little is known about the events that trigger the autoimmune process. Recent epidemiological and experimental data suggest that environmental factors are involved in this process. In this review, we discuss the role of viruses as an environmental factor on the development of type 1 diabetes, and the immune mechanisms by which they can trigger or protect against this pathology.


Assuntos
Diabetes Mellitus Tipo 1/imunologia , Diabetes Mellitus Tipo 1/virologia , Infecções por Enterovirus/imunologia , Infecções por Enterovirus/virologia , Enterovirus/patogenicidade , Células Secretoras de Insulina/imunologia , Animais , Linfócitos B/imunologia , Diabetes Mellitus Tipo 1/etiologia , Diabetes Mellitus Tipo 1/genética , Humanos , Hipótese da Higiene , Células Secretoras de Insulina/virologia , Camundongos , Fatores de Risco , Fatores Socioeconômicos , Linfócitos T/imunologia
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