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1.
Nat Commun ; 10(1): 2498, 2019 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-31175312

RESUMO

Allogeneic mesenchymal stem cells (MSCs) exhibit immunoregulatory function in human autoimmune diseases such as systemic lupus erythematosus (SLE), but the underlying mechanisms remain incompletely understood. Here we show that the number of peripheral tolerogenic CD1c+ dendritic cells (DCs) and the levels of serum FLT3L are significantly decreased in SLE patients especially with lupus nephritis, compared to healthy controls. Transplantation of allogeneic umbilical cord-derived MSCs (UC-MSCs) significantly up-regulates peripheral blood CD1c+DCs and serum FLT3L. Mechanistically, UC-MSCs express FLT3L that binds to FLT3 on CD1c+DCs to promote the proliferation and inhibit the apoptosis of tolerogenic CD1c+DCs. Conversely, reduction of FLT3L with small interfering RNA in MSCs abolishes the up-regulation of tolerogenic CD1c+DCs in lupus patients treated with MSCs. Interferon-γ induces FLT3L expression in UC-MSCs through JAK/STAT signaling pathway. Thus, allogeneic MSCs might suppress inflammation in lupus through up-regulating tolerogenic DCs.


Assuntos
Antígenos CD1/imunologia , Células Dendríticas/imunologia , Glicoproteínas/imunologia , Tolerância Imunológica/imunologia , Lúpus Eritematoso Sistêmico/terapia , Proteínas de Membrana/imunologia , Transplante de Células-Tronco Mesenquimais , Adulto , Antígenos CD1/metabolismo , Estudos de Casos e Controles , Células Dendríticas/metabolismo , Feminino , Glicoproteínas/metabolismo , Humanos , Interferon gama/farmacologia , Janus Quinases/efeitos dos fármacos , Janus Quinases/metabolismo , Lúpus Eritematoso Sistêmico/imunologia , Nefrite Lúpica/imunologia , Nefrite Lúpica/terapia , Masculino , Proteínas de Membrana/metabolismo , Células-Tronco Mesenquimais/efeitos dos fármacos , Células-Tronco Mesenquimais/metabolismo , Pessoa de Meia-Idade , Fatores de Transcrição STAT/efeitos dos fármacos , Fatores de Transcrição STAT/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transplante Homólogo , Adulto Jovem
2.
Immunogenetics ; 71(7): 465-478, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31123763

RESUMO

Invariant NKT (iNKT) cells in both humans and non-human primates are activated by the glycolipid antigen, α-galactosylceramide (α-GalCer). However, the extent to which the molecular mechanisms of antigen recognition and in vivo phenotypes of iNKT cells are conserved among primate species has not been determined. Using an evolutionary genetic approach, we found a lack of diversifying selection in CD1 genes over 45 million years of evolution, which stands in stark contrast to the history of the MHC system for presenting peptide antigens to T cells. The invariant T cell receptor (TCR)-α chain was strictly conserved across all seven primate clades. Invariant NKT cells from rhesus macaques (Macaca mulatta) bind human CD1D-α-GalCer tetramer and are activated by α-GalCer-loaded human CD1D transfectants. The dominant TCR-ß chain cloned from a rhesus-derived iNKT cell line is nearly identical to that found in the human iNKT TCR, and transduction of the rhesus iNKT TCR into human Jurkat cells show that it is sufficient for binding human CD1D-α-GalCer tetramer. Finally, we used a 20-color flow cytometry panel to probe tissue phenotypes of iNKT cells in a cohort of rhesus macaques. We discovered several tissue-resident iNKT populations that have not been previously described in non-human primates but are known in humans, such as TCR-γδ iNKTs. These data reveal a diversity of iNKT cell phenotypes despite convergent evolution of the genes required for lipid antigen presentation and recognition in humans and non-human primates.


Assuntos
Antígenos CD1/genética , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/metabolismo , Primatas/genética , Sequência de Aminoácidos , Animais , Antígenos CD1/metabolismo , Sequência Conservada , Evolução Molecular , Feminino , Humanos , Células Jurkat , Macaca mulatta/imunologia , Masculino , Fenótipo , Primatas/imunologia , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos de Linfócitos T/metabolismo
3.
Mar Drugs ; 17(1)2019 Jan 19.
Artigo em Inglês | MEDLINE | ID: mdl-30669428

RESUMO

In our previous study, we showed that ascophyllan purified from Ascophyllum nodosum treatment promotes mouse dendritic cell (DC) activation in vivo, further induces an antigen-specific immune response and has anticancer effects in mice. However, the effect of ascophyllan has not been studied in human immune cells, specifically in terms of activation of human monocyte-derived DCs (MDDCs) and human peripheral blood DCs (PBDCs). We found that the treatment with ascophyllan induced morphological changes in MDDCs and upregulated co-stimulatory molecules and major histocompatibility complex class I (MHC I) and MHC II expression. In addition, pro-inflammatory cytokine levels in culture medium was also dramatically increased following ascophyllan treatment of MDDCs. Moreover, ascophyllan promoted phosphorylation of ERK, p38 and JNK signaling pathways, and inhibition of p38 almost completely suppressed the ascophyllan-induced activation of MDDCs. Finally, treatment with ascophyllan induced activation of BDCA1 and BDCA3 PBDCs. Thus, these data suggest that ascophyllan could be used as an immune stimulator in humans.


Assuntos
Organismos Aquáticos/química , Ascophyllum/química , Células Dendríticas/efeitos dos fármacos , Imunidade Celular/efeitos dos fármacos , Polissacarídeos/farmacologia , Antígenos CD1/metabolismo , Antígenos de Superfície/metabolismo , Diferenciação Celular , Células Cultivadas , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Glicoproteínas/metabolismo , Voluntários Saudáveis , Antígenos de Histocompatibilidade Classe I/imunologia , Antígenos de Histocompatibilidade Classe I/metabolismo , Antígenos de Histocompatibilidade Classe II/imunologia , Antígenos de Histocompatibilidade Classe II/metabolismo , Humanos , Imunidade Celular/imunologia , Leucócitos Mononucleares , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/imunologia , Fosforilação/efeitos dos fármacos , Polissacarídeos/isolamento & purificação
4.
Front Immunol ; 9: 2709, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30538700

RESUMO

Mycolic acid (MA), a major lipid component of Mycobacterium tuberculosis (Mtb) cell wall, can be presented by the non-polymorphic antigen presenting molecule CD1b to T cells isolated from Mtb-infected individuals. These MA-specific CD1b-restricted T cells are cytotoxic, produce Th1 cytokines, and form memory populations, suggesting that MA can be explored as a potential subunit vaccine candidate for TB. However, the controlled elicitation of MA-specific T cell responses has been challenging due to difficulties in the targeted delivery of lipid antigens and a lack of suitable animal models. In this study, we generated MA-loaded micellar nanocarriers (MA-Mc) comprised of self-assembled poly(ethylene glycol)-bl-poly(propylene sulfide; PEG-PPS) copolymers conjugated to an acid sensitive fluorophore to enhance intracellular delivery of MA to phagocytic immune cells. Using humanized CD1 transgenic (hCD1Tg) mice, we found these nanobiomaterials to be endocytosed by bone marrow-derived dendritic cells (DCs) and localized to lysosomal compartments. Additionally, MA-Mc demonstrated superior efficacy over free MA in activating MA-specific TCR transgenic (DN1) T cells in vitro. Following intranasal immunization, MA-Mc were primarily taken up by alveolar macrophages and DCs in the lung and induced activation and proliferation of adoptively transferred DN1 T cells. Furthermore, intranasal immunization with MA-Mc induced MA-specific T cell responses in the lungs of hCD1Tg mice. Collectively, our data demonstrates that pulmonary delivery of MA via PEG-PPS micelles to DCs can elicit potent CD1b-restricted T cell responses both in vitro and in vivo and MA-Mc could be explored as subunit vaccines against Mtb infection.


Assuntos
Portadores de Fármacos/química , Lipídeos/química , Pulmão/efeitos dos fármacos , Mycobacterium tuberculosis/efeitos dos fármacos , Ácidos Micólicos/farmacologia , Nanopartículas/química , Linfócitos T Citotóxicos/efeitos dos fármacos , Animais , Antígenos de Bactérias/metabolismo , Antígenos CD1/metabolismo , Materiais Biocompatíveis/química , Medula Óssea/efeitos dos fármacos , Medula Óssea/metabolismo , Proliferação de Células/efeitos dos fármacos , Parede Celular/efeitos dos fármacos , Parede Celular/metabolismo , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/metabolismo , Endocitose/efeitos dos fármacos , Humanos , Imunização/métodos , Pulmão/metabolismo , Lisossomos/efeitos dos fármacos , Lisossomos/metabolismo , Macrófagos Alveolares/efeitos dos fármacos , Macrófagos Alveolares/metabolismo , Camundongos , Camundongos Transgênicos , Micelas , Mycobacterium tuberculosis/metabolismo , Polietilenoglicóis/química , Polímeros/química , Sulfetos/química , Linfócitos T Citotóxicos/metabolismo
5.
PLoS One ; 13(4): e0195313, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29652910

RESUMO

There is evidence that dendritic cells (DCs) undergo age-related changes that modulate their function with their key role being priming antigen-specific effector T cells. This occurs once DCs develop into antigen-presenting cells in response to stimuli/danger signals. However, the effects of aging on DC responses to bacterial lipopolysaccharide (LPS), the pro-inflammatory cytokine interferon (IFN)-γ and CD40 ligand (CD40L) have not yet been systematically evaluated. We examined responses of blood myeloid (m)DC1s, mDC2s, plasmacytoid (p)DCs, and monocyte-derived DCs (MoDCs) from young (21-40 years) and elderly (60-84 years) healthy human volunteers to LPS/IFN-γ or CD40L stimulation. All elderly DC subsets demonstrated comparable up-regulation of co-stimulatory molecules (CD40, CD80 and/or CD86), intracellular pro-inflammatory cytokine levels (IFN-γ, tumour necrosis factor (TNF)-α, IL-6 and/or IL-12), and/or secreted cytokine levels (IFN-α, IFN-γ, TNF-α, and IL-12) to their younger counterparts. Furthermore, elderly-derived LPS/IFN-γ or CD40L-activated MoDCs induced similar or increased levels of CD8+ and CD4+ T cell proliferation, and similar T cell functional phenotypes, to their younger counterparts. However, elderly LPS/IFN-γ-activated MoDCs were unreliable in their ability to up-regulate chemokine (IL-8 and monocyte chemoattractant protein (MCP)-1) and IL-6 secretion, implying an inability to dependably induce an inflammatory response. A key age-related difference was that, unlike young-derived MoDCs that completely lost their ability to process antigen, elderly-derived MoDCs maintained their antigen processing ability after LPS/IFN-γ maturation, measured using the DQ-ovalbumin assay; this response implies incomplete maturation that may enable elderly DCs to continuously present antigen. These differences may impact on the efficacy of anti-pathogen and anti-tumour immune responses in the elderly.


Assuntos
Envelhecimento/imunologia , Ligante de CD40/farmacologia , Células Dendríticas/citologia , Células Dendríticas/efeitos dos fármacos , Lipopolissacarídeos/farmacologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígenos CD1/metabolismo , Antígeno B7-2/metabolismo , Antígenos CD40/metabolismo , Células Dendríticas/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fator de Crescimento Transformador beta/metabolismo , Adulto Jovem
6.
Zhonghua Bing Li Xue Za Zhi ; 47(3): 163-167, 2018 Mar 08.
Artigo em Chinês | MEDLINE | ID: mdl-29534353

RESUMO

Objective: To investigate the clinicopathological features, differential diagnosis, and genetic alteration of Langerhans cell sarcoma (LCS). Methods: Four cases of LCS were collected from Fujian Provincial Hospital and Fuzhou General Hospital of Nanjing Military Command of PLA from July 2013 to January 2017. Clinicopathological features and immunophenotype were retrospectively reviewed in four LCS cases combined with genetic mutation analysis of BRAF and ALK. Results: Four cases included 2 women and 2 men with ages from 42 to 79 years (median=59.3 years). The size of the tumors ranged from 2.5-7.8 cm. Histologically, at the low power field, the tumors consisted of highly cellular proliferation in fascicules, whirlpool and diffuse sheets arrangement. The tumor cells were kidney-or horseshoe-shaped to round epithelioid cells or enlarged spindle cells. The neoplastic cells showed cytological atypia, hyperchromatic nuclei with prominent 1 to 2 nucleoli. Multinucleated giant cells were also found. Mitotic activity was approximately (50-70) mitoses/10 HPF. Immunohistochemically, the tumor cells were positive for S-100 protein (4/4), SOX10(3/4), Langerin/CD207(4/4), CD1a(3/4), CD68(3/4), CD163(3/4), and INI-1(4/4). Ki-67 index was 30%-80%. Gene mutation analysis showed that one case had BRAF V600E mutation but none had ALK gene alteration. Conclusions: LCS is a rare tumor with highly malignant potential and distinct morphologic features.The primary treatment for LCS is completely surgical excision and chemotherapy. The prognosis is generally poor.


Assuntos
Sarcoma de Células de Langerhans/patologia , Adulto , Idoso , Antígenos CD/metabolismo , Antígenos CD1/metabolismo , Antígenos de Diferenciação Mielomonocítica/metabolismo , Células Epitelioides/patologia , Feminino , Células Gigantes/patologia , Humanos , Imunofenotipagem , Sarcoma de Células de Langerhans/genética , Sarcoma de Células de Langerhans/metabolismo , Masculino , Pessoa de Meia-Idade , Mitose , Mutação , Prognóstico , Receptores de Superfície Celular/metabolismo , Estudos Retrospectivos , Proteínas S100/metabolismo , Proteína SMARCB1/metabolismo , Carga Tumoral
7.
J Immunol ; 200(2): 500-511, 2018 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-29237773

RESUMO

In humans, a substantial portion of T cells recognize lipids presented by the monomorphic CD1 proteins. Recent studies have revealed the molecular basis of mycobacterial lipid recognition by CD1c-restricted T cells. Subsets of CD1c-restricted T cells recognize self-lipids in addition to foreign lipids, which may have implications in human diseases involving autoimmunity and malignancy. However, the molecular identity of these self-reactive T cells remains largely elusive. In this study, using a novel CD1c+ artificial APC (aAPC)-based system, we isolated human CD1c-restricted autoreactive T cells and characterized them at the molecular level. By using the human cell line K562, which is deficient in MHC class I/II and CD1 expression, we generated an aAPC expressing CD1c as the sole Ag-presenting molecule. When stimulated with this CD1c+ aAPC presenting endogenous lipids, a subpopulation of primary CD4+ T cells from multiple donors was consistently activated, as measured by CD154 upregulation and cytokine production in a CD1c-specific manner. These activated CD4+ T cells preferentially expressed TRBV4-1+ TCRs. Clonotypic analyses of the reconstituted TRBV4-1+ TCR genes confirmed CD1c-restricted autoreactivity of this repertoire, and the strength of CD1c reactivity was influenced by the diversity of CDR3ß sequences. Finally, alanine scanning of CDR1 and CDR2 sequences of TRBV4-1 revealed two unique residues, Arg30 and Tyr51, as critical in conferring CD1c-restricted autoreactivity, thus elucidating the molecular basis of the observed V gene bias. These data provide new insights into the molecular identity of human autoreactive CD1c-restricted T cells.


Assuntos
Antígenos CD1/imunologia , Antígenos CD1/metabolismo , Autoimunidade , Expressão Gênica , Genes Codificadores da Cadeia beta de Receptores de Linfócitos T , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Apresentação do Antígeno/imunologia , Células Apresentadoras de Antígenos/imunologia , Células Apresentadoras de Antígenos/metabolismo , Arginina/genética , Biomarcadores , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Linhagem Celular , Evolução Clonal/genética , Evolução Clonal/imunologia , Códon , Regiões Determinantes de Complementaridade/genética , Humanos , Imunofenotipagem , Ativação Linfocitária , Fenótipo , Tirosina/genética
8.
Acta Derm Venereol ; 98(1): 50-58, 2018 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-28853491

RESUMO

Differential diagnosis of palmoplantar non-pustular psoriasis and chronic allergic contact dermatitis (ACD) and the combination of these conditions, termed "eczema in psoriatico" (EIP), is difficult, especially in cases of isolated involvement. A blind re-evaluation of 63 archived formalin-fixed palmoplantar samples, previously diagnosed clinically as either psoriasis or chronic ACD, was performed. Samples were allocated to histopathological diagnoses of psoriasis, contact dermatitis or EIP. Immunohistological stainings were performed for better characterization. Immunochemistry of EIP revealed features that overlapped contemporarily with psoriasis (cytokeratin 17 (CK17), Ki67, interleukin (IL)-8, IL-17, IL-23) and with ACD (CD1a, major histocompatibility complex (MHC) class I, MHC class II, epidermal T-cell subsets). Surprisingly, a significantly much higher number of dermal CD8+ T cells was found in EIP than in ACD and psoriasis. In conclusion, this study provides insight into the immunohistological differentiation of palmoplantar psoriasis, chronic ACD and EIP.


Assuntos
Dermatite Alérgica de Contato/diagnóstico , Dermatite Alérgica de Contato/metabolismo , Interleucinas/metabolismo , Psoríase/diagnóstico , Psoríase/metabolismo , Antígenos CD1/metabolismo , Linfócitos T CD8-Positivos/patologia , Doença Crônica , Dermatite Alérgica de Contato/complicações , Dermatite Alérgica de Contato/patologia , Diagnóstico Diferencial , Antígenos de Histocompatibilidade Classe I/metabolismo , Antígenos de Histocompatibilidade Classe II/metabolismo , Humanos , Imunoglobulina E/sangue , Imuno-Histoquímica , Proteínas de Filamentos Intermediários/metabolismo , Queratina-17/metabolismo , Antígeno Ki-67/metabolismo , Contagem de Linfócitos , Psoríase/complicações , Psoríase/patologia , Subpopulações de Linfócitos T/patologia
9.
J Matern Fetal Neonatal Med ; 31(7): 901-906, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28298162

RESUMO

PURPOSE: Dendritic cells (DCs) are involved in immune system, which can also regulate the differentiation of T helper 17 (Th17) and regulatory T cells (Treg). DCs and Th17/Treg participate in preeclampsia and recurrent spontaneous abortion (RSA), but there is still lack of research in intrahepatic cholestasis of pregnancy (ICP). The aim was to evaluate the expression and significance of CD83+DCs, CD1a+DCs, interleukin-17 (IL-17) and IL-35 in serum and placental tissues of patients with ICP. METHODS: Thirty cases of mild ICP, 25 cases of severe ICP were selected, and 30 cases of normal pregnant women were selected as control group. Enzyme-linked immunosorbent assay (ELISA) and immunohistochemistry (IHC) were used to detect the expression of CD83+DCs, CD1a+DCs, IL-17 and IL-35 in serum and placenta tissues, respectively. RESULTS: There were more CD83+DCs, IL-17 expressed in placenta from women with ICP than in normal pregnancies, while the number of decidual CD1a+DCs, IL-35 was significantly lower in ICP than in normal pregnant women. The comparison within three groups had statistical difference (p < .05). Serum CD83+DCs and CD1a+DCs levels had no significance. IL-17 was higher in ICP, while IL-35 was lower. CONCLUSIONS: DCs are involved in damaging the maternal-fetal immune tolerance by changing the phenotype and mature state, which may affect the differentiation of Th17/Treg to cause ICP.


Assuntos
Antígenos CD1/metabolismo , Colestase Intra-Hepática/imunologia , Células Dendríticas/imunologia , Placenta/imunologia , Complicações na Gravidez/imunologia , Células Th17/imunologia , Análise de Variância , Antígenos CD/metabolismo , Antígenos CD1/genética , Estudos de Casos e Controles , Colestase Intra-Hepática/sangue , Colestase Intra-Hepática/classificação , Células Dendríticas/citologia , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Imunoglobulinas/metabolismo , Interleucina-17/genética , Interleucina-17/metabolismo , Glicoproteínas de Membrana/metabolismo , Placenta/patologia , Gravidez , Complicações na Gravidez/sangue , Complicações na Gravidez/classificação
10.
Microb Pathog ; 113: 152-159, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29074429

RESUMO

Vibrio ichthyoenteri was an important causative agent of bacterial enteritis in flounder (Paralichthys olivaceus). Outer membrane protein A (OmpA) of Gram-negative pathogen was a major cell surface antigen. In the present study, OmpA of V. ichthyoenteri was recombinantly expressed in Escherichia coli, and the immunogenicity of OmpA was identified by western blotting using flounder anti-rOmpA and anti-V. ichthyoenteri antibodies. The vaccine potential of rOmpA was tested in a flounder model, and a high relative percentage of survival rate was obtained with 73.1% after challenge with V. ichthyoenteri. Meanwhile, the immune response of flounder induced by rOmpA was also investigated, and the results showed that the sIg + lymphocytes in blood, spleen, and pronephros significantly proliferated, and the peak levels occurred at week 4 after immunization. Moreover, rOmpA could induce higher levels of specific serum antibodies than the control group after immunization, and the peak level occurred at week 5 after immunization. Meanwhile, qRT-PCR analysis showed that the expressions of CD4-1, CD8α, IL-1ß, IFN-γ, MHCIα and MHCIIα genes were significantly up-regulated after immunization with rOmpA. Taking together, these results demonstrated that rOmpA could evoke highly protective effects against V. ichthyoenteri challenge and induce strong immune response of flounder, which indicated that OmpA was a promising vaccine candidate.


Assuntos
Proteínas da Membrana Bacteriana Externa/imunologia , Vacinas Bacterianas/imunologia , Doenças dos Peixes/prevenção & controle , Linguado/imunologia , Imunização , Vibrioses/prevenção & controle , Vibrioses/veterinária , Vibrio/imunologia , Imunidade Adaptativa/imunologia , Animais , Anticorpos Antibacterianos/sangue , Anticorpos Antibacterianos/imunologia , Antígenos de Bactérias/genética , Antígenos CD1/genética , Antígenos CD1/metabolismo , Antígenos de Superfície/imunologia , Proteínas da Membrana Bacteriana Externa/genética , Vacinas Bacterianas/genética , Antígenos CD4/genética , Antígenos CD4/metabolismo , Antígenos CD8/genética , Antígenos CD8/metabolismo , Modelos Animais de Doenças , Escherichia coli/genética , Doenças dos Peixes/imunologia , Linguado/microbiologia , Regulação Bacteriana da Expressão Gênica , Genes MHC Classe I/fisiologia , Genes MHC da Classe II/fisiologia , Imunidade Inata/imunologia , Interferon gama/metabolismo , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Linfócitos/imunologia , Proteínas Recombinantes/genética , Proteínas Recombinantes/imunologia , Taxa de Sobrevida , Vacinação , Vacinas de DNA/genética , Vacinas de DNA/imunologia , Vibrioses/imunologia
11.
Sci Immunol ; 2(16)2017 10 20.
Artigo em Inglês | MEDLINE | ID: mdl-29054999

RESUMO

Human T cell autoreactivity toward lipid antigens presented by CD1 proteins can manifest in numerous diseases, including psoriasis, contact hypersensitivities, and allergies. However, the molecular mechanisms for regulating T cell autoreactivity toward lipid antigens remain unclear. We determined the basis for T cell receptor (TCR) autoreactivity toward CD1b bound to self-phospholipids. The spectrum of self-antigens captured by CD1b skews toward abundant membrane phospholipids such as phosphatidylcholine and phosphatidylethanolamine. However, TCRs can specifically recognize rare phospholipids, including phosphatidylglycerol (PG). The structure of an autoreactive TCR bound to CD1b-PG shows that discrimination occurs through a marked induced fit movement of PG so that its polar head group fits snugly into the cationic cup of the TCR. Conversely, TCR binding toward ubiquitous self-phospholipids was sterically or electrostatically repelled. Accordingly, we describe a mechanism of TCR autoreactivity toward rare phospholipids and avoidance of autoreactivity to the most abundant self-phospholipids.


Assuntos
Autoantígenos/imunologia , Fosfolipídeos/imunologia , Receptores de Antígenos de Linfócitos T alfa-beta/imunologia , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos de Linfócitos T/imunologia , Animais , Antígenos CD1/imunologia , Antígenos CD1/metabolismo , Humanos , Células K562 , Ativação Linfocitária , Camundongos , Fosfatidilcolinas/imunologia , Fosfatidilcolinas/metabolismo , Fosfatidiletanolaminas/imunologia , Fosfatidiletanolaminas/metabolismo , Fosfolipídeos/química , Fosfolipídeos/metabolismo , Psoríase/imunologia , Receptores de Antígenos de Linfócitos T/química , Receptores de Antígenos de Linfócitos T/fisiologia , Receptores de Antígenos de Linfócitos T alfa-beta/química , Receptores de Antígenos de Linfócitos T alfa-beta/genética , Linfócitos T/imunologia
12.
Blood ; 130(17): 1898-1902, 2017 10 26.
Artigo em Inglês | MEDLINE | ID: mdl-28847997

RESUMO

Langerhans cell histiocytosis (LCH) is a rare disease with an unknown etiology characterized by heterogeneous lesions containing CD207+CD1a+ cells that can arise in almost any tissue and cause significant morbidity and mortality. Precursors of pathological Langerhans cells have yet to be defined. Our aim was to identify circulating CD207+CD1a+ cells and their inducers in LCH. Expression of CD207 and CD1a in the blood myeloid compartment as well as thymic stromal lymphopoietin (TSLP) and transforming growth factor ß (TGF-ß) plasma levels were measured in 22 pediatric patients with active disease (AD) or nonactive disease (NAD). In patients with AD vs those with NAD, the myeloid compartment showed an increased CD11b (CD11bhigh plus CD11b+) fraction (39.7 ± 3.6 vs 18.6 ± 1.9), a higher percentage of circulating CD11bhighCD11c+CD207+ cells (44.5 ± 11.3 vs 3.2 ± 0.5), and the presence of CD11chighCD207+CD1a+ cells (25.0 ± 9.1 vs 2.3 ± 0.5). Blood CD207+CD1a+ cells were not observed in adult controls or umbilical cord. Increased TSLP and TGF-ß levels were detected in patients with AD. Interestingly, plasma from patients with AD induces CD207 expression on CD14+ monocytes. We conclude that CD207+CD1a+ cells are circulating in patients with active LCH, and TSLP and TGF-ß are potential drivers of Langerhans-like cells in vivo.


Assuntos
Antígenos CD1/metabolismo , Antígenos CD/metabolismo , Histiocitose de Células de Langerhans/metabolismo , Histiocitose de Células de Langerhans/patologia , Lectinas Tipo C/metabolismo , Lectinas de Ligação a Manose/metabolismo , Criança , Pré-Escolar , Citocinas/sangue , Feminino , Histiocitose de Células de Langerhans/sangue , Humanos , Lactente , Masculino , Fator de Crescimento Transformador beta/sangue
13.
Curr Opin Immunol ; 46: 127-133, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28756303

RESUMO

CD1a, CD1b, CD1c and CD1d proteins migrate through distinct subcellular compartments of antigen presenting cells and so can be considered to take four separate pathways leading to display of lipid antigens to T cell receptors. This review discusses the intersection of CD1 trafficking and lipid antigen loading mechanisms in cells, highlighting key controversies relating to CD1 gene expression, size mismatches between antigens and CD1 binding clefts and unexpected mechanisms of T cell receptor-based recognition.


Assuntos
Apresentação do Antígeno/imunologia , Antígenos CD1/imunologia , Antígenos CD1/metabolismo , Transdução de Sinais , Linfócitos T/imunologia , Linfócitos T/metabolismo , Animais , Apresentação do Antígeno/genética , Células Apresentadoras de Antígenos/imunologia , Células Apresentadoras de Antígenos/metabolismo , Antígenos CD1/química , Antígenos CD1/genética , Regulação da Expressão Gênica , Antígenos de Histocompatibilidade Classe I/imunologia , Antígenos de Histocompatibilidade Classe I/metabolismo , Antígenos de Histocompatibilidade Classe II/imunologia , Antígenos de Histocompatibilidade Classe II/metabolismo , Humanos , Metabolismo dos Lipídeos , Lipídeos/imunologia , Ligação Proteica/imunologia , Receptores de Antígenos de Linfócitos T/metabolismo
14.
Eur J Immunol ; 47(9): 1525-1534, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-28665555

RESUMO

Mycobacterium tuberculosis synthesizes a thick cell wall comprised of mycolic acids (MA), which are foreign antigens for human T cells. T-cell clones from multiple donors were used to determine the fine specificity of MA recognition by human αß T cells. Most CD1-presented lipid antigens contain large hydrophilic head groups comprised of carbohydrates or peptides that dominate patterns of T-cell specificity. MA diverges from the consensus antigen motif in that it lacks a head group. Using multiple forms of natural and synthetic MA and MA-specific T-cells with different T-cell receptors, we found that, unlike antigens with larger head groups, lipid length strongly controlled T-cell responses to MA. In addition, the three forms of MA that naturally occur in M. tuberculosis that differ in modifications on the lipid tail, differ in their potency for activating MA-specific T-cell clones. Thus, naturally occurring MA forms should be considered as separate, partly cross-reactive antigens. Two of the three forms of MA could be loaded onto human CD1b proteins, creating working CD1b-MA tetramers. The creation of CD1b-MA tetramers represents a new tool for future studies that track the effector functions and kinetics of MA-specific T-cells ex vivo.


Assuntos
Antígenos de Bactérias/metabolismo , Antígenos CD1/metabolismo , Parede Celular/metabolismo , Mycobacterium tuberculosis/imunologia , Ácidos Micólicos/metabolismo , Especificidade do Receptor de Antígeno de Linfócitos T , Linfócitos T/imunologia , Antígenos de Bactérias/imunologia , Células Clonais , Reações Cruzadas , Humanos , Técnicas Imunológicas , Lipídeos/química , Ativação Linfocitária , Ácidos Micólicos/química , Ácidos Micólicos/imunologia , Ligação Proteica , Receptores de Antígenos de Linfócitos T alfa-beta/genética , Receptores de Antígenos de Linfócitos T alfa-beta/metabolismo , Linfócitos T/microbiologia
15.
PLoS One ; 12(7): e0180333, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28704477

RESUMO

Antigen exposure to oral mucosa is generally thought to lead to immune tolerance induction. However, very little is known about the subset composition and function of dendritic cells (DC) migrating from human oral mucosa. Here we show that migratory DC from healthy human gingival explants consist of the same phenotypic subsets in the same frequency distribution as DC migrating from human skin. The gingival CD1a+ Langerhans cell and interstitial DC subsets lacked CXCR4 expression in contrast to their cutaneous counterparts, pointing to different migration mechanisms, consistent with previous observations in constructed skin and gingival equivalents. Remarkably, without any exogenous conditioning, gingival explants released higher levels of inflammatory cytokines than human skin explants, resulting in higher DC migration rates and a superior ability of migrated DC to prime allogeneic T cells and to induce type-1 effector T cell differentiation. From these observations we conclude that rather than an intrinsic ability to induce T cell tolerance, DC migrating from oral mucosa may have a propensity to induce effector T cell immunity and maintain a high state of alert against possible pathogenic intruders in the steady state. These findings may have implications for oral immunization strategies.


Assuntos
Células Dendríticas/citologia , Mucosa Bucal/citologia , Receptores CXCR4/metabolismo , Pele/citologia , Antígenos CD1/metabolismo , Diferenciação Celular , Movimento Celular , Citocinas/metabolismo , Células Dendríticas/imunologia , Humanos , Células de Langerhans/citologia , Células de Langerhans/imunologia , Mucosa Bucal/metabolismo , Fenótipo , Pele/metabolismo , Linfócitos T/imunologia
16.
Immunol Cell Biol ; 95(9): 753-764, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-28559542

RESUMO

Given the heterogeneous nature of antigens, major histocompatibility complex class I (MHC I) intracellular transport intersects with multiple degradation pathways for efficient peptide loading and presentation to cytotoxic T cells. MHC I loading with peptides in the endoplasmic reticulum (ER) is a tightly regulated process, while post-ER intracellular transport is considered to occur by default, leading to peptide-bearing MHC I delivery to the plasma membrane. We show here that MHC I traffic is submitted to a previously uncharacterized sorting step at the trans Golgi network (TGN), dependent on the ubiquitination of its cytoplasmic tail lysine residues. MHC I ubiquitination is mediated by the E3 ligase membrane-associated RING-CH 9 (MARCH9) and allows MHC I access to Syntaxin 6-positive endosomal compartments. We further show that MARCH9 can also target the human MHC I-like lipid antigen-presentation molecule CD1a. MARCH9 expression is modulated by microbial pattern exposure in dendritic cells (DCs), thus revealing the role of this ubiquitin E3 ligase in coordinating MHC I access to endosomes and DC activation for efficient antigen cross-presentation.


Assuntos
Antígenos CD1/metabolismo , Membrana Celular/metabolismo , Células Dendríticas/imunologia , Endossomos/metabolismo , Antígenos HLA/metabolismo , Antígenos de Histocompatibilidade Classe I/metabolismo , Rede trans-Golgi/metabolismo , Apresentação do Antígeno , Antígenos CD1/genética , Células Cultivadas , Retículo Endoplasmático/metabolismo , Antígenos HLA/genética , Antígenos de Histocompatibilidade Classe I/genética , Humanos , Proteínas de Membrana , Monócitos/imunologia , Domínios Proteicos/genética , Sinais Direcionadores de Proteínas/genética , Transporte Proteico , Proteínas Qa-SNARE/metabolismo , Ubiquitina-Proteína Ligases , Ubiquitinação
17.
Neuropharmacology ; 121: 140-157, 2017 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-28461162

RESUMO

Neurotrophic factors are among the most promising treatments aiming at slowing or stopping and even reversing Parkinson's disease (PD). However, in most cases, they cannot readily cross the human blood-brain-barrier (BBB). Herein, we propose as a therapeutic for PD the small molecule 17-beta-spiro-[5-androsten-17,2'-oxiran]-3beta-ol (BNN-20), a synthetic analogue of DHEA, which crosses the BBB and is deprived of endocrine side-effects. Using the "weaver" mouse, a genetic model of PD, which exhibits progressive dopaminergic neurodegeneration in the Substantia Nigra (SN), we have shown that long-term administration (P1-P21) of BNN-20 almost fully protected the dopaminergic neurons and their terminals, via i) a strong anti-apoptotic effect, probably mediated through the Tropomyosin receptor kinase B (TrkB) neurotrophin receptor's PI3K-Akt-NF-κB signaling pathway, ii) by exerting an efficient antioxidant effect, iii) by inducing significant anti-inflammatory activity and iv) by restoring Brain-Derived Neurotrophic Factor (BDNF) levels. By intercrossing "weaver" with NGL mice (dual GFP/luciferase-NF-κΒ reporter mice, NF-κΒ.GFP.Luc), we obtained Weaver/NGL mice that express the NF-κB reporter in all somatic cells. Acute BNN-20 administration to Weaver/NGL mice induced a strong NF-κB-dependent transcriptional response in the brain as detected by bioluminescence imaging, which was abolished by co-administration of the TrkB inhibitor ANA-12. This indicates that BNN-20 exerts its beneficial action (at least in part) through the TrkB-PI3K-Akt-NF-κB signaling pathway. These results could be of clinical relevance, as they suggest BNN-20 as an important neuroprotective agent acting through the TrkB neurotrophin receptor pathway, mimicking the action of the endogenous neurotrophin BDNF. Thus BNN-20 could be proposed for treatment of PD.


Assuntos
Desidroepiandrosterona/análogos & derivados , Dopamina/metabolismo , Neurônios Dopaminérgicos/efeitos dos fármacos , Mesencéfalo/citologia , Receptor trkB/metabolismo , Adjuvantes Imunológicos/farmacologia , Animais , Animais Recém-Nascidos , Antígenos CD1/metabolismo , Azepinas/farmacologia , Benzamidas/farmacologia , Células CHO , Cricetulus , Desidroepiandrosterona/farmacologia , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Feminino , Masculino , Mesencéfalo/efeitos dos fármacos , Mesencéfalo/metabolismo , Camundongos , Camundongos Mutantes Neurológicos , Modelos Genéticos , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Tubulina (Proteína)/metabolismo , Tirosina 3-Mono-Oxigenase/metabolismo
18.
J Clin Invest ; 127(6): 2339-2352, 2017 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-28463230

RESUMO

A large proportion of human T cells are autoreactive to group 1 CD1 proteins, which include CD1a, CD1b, and CD1c. However, the physiological role of the CD1 proteins remains poorly defined. Here, we have generated a double-transgenic mouse model that expresses human CD1b and CD1c molecules (hCD1Tg) as well as a CD1b-autoreactive TCR (HJ1Tg) in the ApoE-deficient background (hCD1Tg HJ1Tg Apoe-/- mice) to determine the role of CD1-autoreactive T cells in hyperlipidemia-associated inflammatory diseases. We found that hCD1Tg HJ1Tg Apoe-/- mice spontaneously developed psoriasiform skin inflammation characterized by T cell and neutrophil infiltration and a Th17-biased cytokine response. Anti-IL-17A treatment ameliorated skin inflammation in vivo. Additionally, phospholipids and cholesterol preferentially accumulated in diseased skin and these autoantigens directly activated CD1b-autoreactive HJ1 T cells. Furthermore, hyperlipidemic serum enhanced IL-6 secretion by CD1b+ DCs and increased IL-17A production by HJ1 T cells. In psoriatic patients, the frequency of CD1b-autoreactive T cells was increased compared with that in healthy controls. Thus, this study has demonstrated the pathogenic role of CD1b-autoreactive T cells under hyperlipidemic conditions in a mouse model of spontaneous skin inflammation. As a large proportion of psoriatic patients are dyslipidemic, this finding is of clinical significance and indicates that self-lipid-reactive T cells might serve as a possible link between hyperlipidemia and psoriasis.


Assuntos
Antígenos CD1/metabolismo , Dermatite/imunologia , Hiperlipidemias/imunologia , Psoríase/imunologia , Linfócitos T/imunologia , Animais , Células Cultivadas , Técnicas de Cocultura , Humanos , Hiperlipidemias/complicações , Ativação Linfocitária , Camundongos Knockout , Infiltração de Neutrófilos , Pele/imunologia , Pele/patologia
19.
PLoS One ; 12(5): e0176793, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28463985

RESUMO

Palmitic acid (PA) and other saturated fatty acids are known to stimulate pro-inflammatory responses in human immune cells via Toll-like receptor 4 (TLR4). However, the molecular mechanism responsible for fatty acid stimulation of TLR4 remains unknown. Here, we demonstrate that PA functions as a ligand for TLR4 on human monocyte derived dendritic cells (MoDCs). Hydrophobicity protein modeling indicated PA can associate with the hydrophobic binding pocket of TLR4 adaptor protein MD-2. Isothermal titration calorimetry quantified heat absorption that occurred during PA titration into TLR4/MD2, indicating that PA binds to TLR4/MD2. Treatment of human MoDCs with PA resulted in endocytosis of TLR4, further supporting the function of PA as a TLR4 agonist. In addition, PA stimulated DC maturation and activation based on the upregulation of DC costimulatory factors CD86 and CD83. Further experiments showed that PA induced TLR4 dependent secretion of the pro-inflammatory cytokine IL-1ß. Lastly, our experimental data show that PA stimulation of NF-κB canonical pathway activation is regulated by TLR4 signaling and that reactive oxygen species may be important in upregulating this pro-inflammatory response. Our experiments demonstrate for the first time that PA activation of TLR4 occurs in response to direct molecular interactions between PA and MD-2. In summary, our findings suggest a likely molecular mechanism for PA induction of pro-inflammatory immune responses in human dendritic cells expressing TLR4.


Assuntos
Células Dendríticas/imunologia , Interleucina-1beta/metabolismo , Ácido Palmítico/metabolismo , Receptor 4 Toll-Like/metabolismo , Antígenos CD/metabolismo , Antígenos CD1/metabolismo , Antígeno B7-2/metabolismo , Sítios de Ligação , Caspase 1/metabolismo , Células Cultivadas , Células Dendríticas/citologia , Relação Dose-Resposta a Droga , Células HeLa , Humanos , Interações Hidrofóbicas e Hidrofílicas , Imunoglobulinas/metabolismo , Fatores Imunológicos/administração & dosagem , Antígeno 96 de Linfócito/metabolismo , Glicoproteínas de Membrana/metabolismo , Simulação de Acoplamento Molecular , NF-kappa B/metabolismo , Ácido Palmítico/administração & dosagem , Espécies Reativas de Oxigênio/metabolismo , Proteínas Recombinantes/metabolismo
20.
Arch Immunol Ther Exp (Warsz) ; 65(3): 201-214, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28386696

RESUMO

Contrary to general view that the MHC Class I and II are the kapellmeisters of recognition and response to antigens, there is another big player in that part of immunity, represented by CD1 glycoproteins. In contrast to MHC Class I or II, which present peptides, CD1 molecules present lipids. Humans express five CD1 proteins (CD1a-e), four of which (CD1a-d) are trafficked to the cell surface, where they may display lipid antigens to T-cell receptors. This interaction may lead to both non-cognate and cognate T cell help to B cells, the latter eliciting anti-lipid antibody response. All CD1 proteins can bind a broad range of structurally different exogenous and endogenous lipids, but each shows a preference to one or more lipid classes. This unorthodox binding behavior is the result of elaborate architectures of CD1 binding clefts and distinct intracellular trafficking routes. Together, these features make CD1 system a versatile player in immune response, sitting at the crossroads of innate and adaptive immunity. While CD1 system may be involved in numerous infectious, inflammatory, and autoimmune diseases, its involvement may lead to opposite outcomes depending on different pathologies. Despite these ambiguities and complexity, CD1 system draws growing attention and continues to show glimmers of therapeutic potential. In this review, we summarize the current knowledge about CD1 proteins, their structures, lipid-binding profiles, and roles in immunity, and evaluate the role of CD1 proteins in eliciting humoral immune response.


Assuntos
Apresentação do Antígeno , Antígenos CD1/metabolismo , Linfócitos B/imunologia , Células T Matadoras Naturais/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Imunidade Adaptativa , Animais , Antígenos/imunologia , Antígenos/metabolismo , Antígenos CD1/imunologia , Glicoesfingolipídeos/imunologia , Glicoesfingolipídeos/metabolismo , Humanos , Imunidade Humoral , Imunidade Inata , Ativação Linfocitária , Comunicação Parácrina , Receptores de Antígenos de Linfócitos T/metabolismo
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