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1.
Am J Respir Cell Mol Biol ; 63(4): 464-477, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32543909

RESUMO

By enhancing tissue repair and modulating immune responses, Foxp3+ regulatory T cells (Tregs) play essential roles in resolution from lung injury. The current study investigated the effects that Tregs exert directly or indirectly on the transcriptional profiles of type 2 alveolar epithelial (AT2) cells during resolution in an experimental model of acute lung injury. Purified AT2 cells were isolated from uninjured mice or mice recovering from LPS-induced lung injury, either in the presence of Tregs or in Treg-depleted mice, and transcriptome profiling identified differentially expressed genes. Depletion of Tregs resulted in altered expression of 49 genes within AT2 cells during resolution, suggesting that Tregs present in this microenvironment influence AT2-cell function. Biological processes from Gene Ontology enriched in the absence of Tregs included those describing responses to IFN. Neutralizing IFN-γ in Treg-depleted mice reversed the effect of Treg depletion on inflammatory macrophages and B cells by preventing the increase in inflammatory macrophages and the decrease in B cells. Our results provide insight into the effects of Tregs on AT2 cells. Tregs directly or indirectly impact many AT2-cell functions, including IFN type I and II-mediated signaling pathways. Inhibition of IFN-γ expression and/or function may be one mechanism through which Tregs accelerate resolution after acute lung injury.


Assuntos
Lesão Pulmonar Aguda/imunologia , Células Epiteliais Alveolares/imunologia , Interferon gama/imunologia , Pulmão/imunologia , Linfócitos T Reguladores/imunologia , Transcriptoma/imunologia , Animais , Linfócitos B/imunologia , Feminino , Fatores de Transcrição Forkhead/imunologia , Inflamação/imunologia , Macrófagos/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Transdução de Sinais/imunologia
2.
Mol Immunol ; 124: 1-8, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32480291

RESUMO

Regulatory T cells (Tregs) is one of the immunosuppressive subsets of CD4+ T cells characterized by transcription factor forkhead box protein P3 (FOXP3) expression which are involved in tumor development and progression. Identification of the factors that influence Treg cell function is extremely important. Our current study aimed to evaluate the frequency of Treg cells, cytokine secretion and the expression of microRNAs (miRNAs) in pediatric acute lymphoblastic leukemia (ALL) patients. The frequency of CD3+, CD4+ and CD4+CD25+FOXP3+ Treg was assessed by flow cytometry in 43 ALL patients versus 42 controls. Plasma levels of IL-10, transcription factor ß (TGF-ß), IL-6, IL-17, IL-23 and tumor necrosis factor (TNF-α) were measured by Enzyme-linked immunosorbent assay (ELISA). miR-21, miR-24, miR-26a, miR133b, miR-148a and miR-155 expression were analyzed using quantitative real-time polymerase chain reaction (qRT-PCR). A slight insignificant increase in Treg cells in ALL patients compared to controls was observed. There was a significant elevation in IL-10 (p < 0.05), IL-6 (p < 0.01), IL-23 (p < 0.05) and TNF-α (p < 0.01) in ALL patients compared with controls. Meanwhile, a significant reduction in TGF-ß (p < 0.001) was recorded. A slight insignificant decrease in IL-17 in ALL patients was observed.ALL patients showed a significant increase in miR-21 (p < 0.05), miR-148a (p < 0.01), miR-24 (p < 0.05) and a significant reduction in miR-155 (p < 0.01). In conclusion, the slight change in Treg cells frequency and alteration in related cytokines could possibly involve in the pathogenesis of ALL. Dysregulated miRNAs, as a regulatory mechanism of epigenetics, might contribute to these observed results. Further researches are required to confirm our interesting findings.


Assuntos
Citocinas/imunologia , MicroRNAs/imunologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/imunologia , Linfócitos T Reguladores/imunologia , Criança , Pré-Escolar , Feminino , Fatores de Transcrição Forkhead/imunologia , Regulação da Expressão Gênica/imunologia , Humanos , Lactente , Subunidade alfa de Receptor de Interleucina-2/imunologia , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética
3.
Biochem Biophys Res Commun ; 527(4): 909-914, 2020 07 05.
Artigo em Inglês | MEDLINE | ID: mdl-32430172

RESUMO

Foxp3+ regulatory T cells (Tregs) are essential for the prevention of autoantibody and allergen-specific IgE production. Treg deficiency causes an elevation of the serum levels of these pathogenic antibodies, accompanied by spontaneous germinal center (GC) formation. However, it remains to be determined whether excessive and pathogenic antibody production induced by Treg deficiency requires a GC response. Here, we demonstrate that spontaneous antibody production observed in Foxp3 conditional-knockout mice did not need GC formation. Foxp3 and Bcl6 conditional-double knockout mice exhibited spontaneous elevations of IgG1, IgG2c, and IgE levels even though they showed impaired production of IgG1 and IgE specific for the immunized antigen. Furthermore, the IgG1 and IgE antibodies specific for auto- and food-antigens were produced independently of GCs. These data suggested that a GC response was unnecessary for pathogenic antibody production caused by Treg deficiency.


Assuntos
Formação de Anticorpos , Linfócitos T Reguladores/imunologia , Animais , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/imunologia , Centro Germinativo/imunologia , Imunoglobulina E/imunologia , Imunoglobulina G/imunologia , Camundongos Endogâmicos C57BL , Camundongos Knockout
4.
Cancer Sci ; 111(8): 3032-3044, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32449240

RESUMO

Tumor location and immunity play important roles in the progression of colorectal cancer (CRC). This study aimed to investigate the differences in the immunosurveillance pattern between right- and left-sided CRC and analyze their association with clinicopathologic features, including mismatch repair (MMR) status. We included surgically resected stage II/III CRC cases and evaluated the immunohistochemical findings of HLA class I, HLA class II, programmed cell death-ligand 1 (PD-L1), PD-1, CTLA-4, CD3, CD4, CD8, TIA-1, T-bet, GATA3, RORγT, Foxp3, and CD163. A total of 117 patients were included in the analyses; of these, 30 and 87 had right- and left-sided cancer, respectively. Tumor immunity varied according to the tumor location in the overall cohort. Analysis of the tumors excluding those with DNA mismatch repair (MMR) deficiency also revealed that tumor immunity differed according to the tumor location. In right-sided colon cancer (CC), high expression of Foxp3 (P = .0055) and TIA-1 (P = .0396) were associated with significantly better disease-free survival (DFS). High CD8 (P = .0808) and CD3 (P = .0863) expression tended to have better DFS. Furthermore, in left-sided CRC, only high PD-L1 expression in the stroma (P = .0426) was associated with better DFS. In multivariate analysis, high Foxp3 expression in right-sided CC was an independent prognostic factor for DFS (hazard ratio, 7.6445; 95% confidence interval, 1.2091-150.35; P = .0284). In conclusion, the immunosurveillance pattern differs between right- and left-sided CRC, even after adjusting for MMR deficiency.


Assuntos
Biomarcadores Tumorais/metabolismo , Neoplasias Colorretais/imunologia , Reparo de Erro de Pareamento de DNA/imunologia , Vigilância Imunológica/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígeno B7-H1/imunologia , Antígeno B7-H1/metabolismo , Biomarcadores Tumorais/imunologia , Complexo CD3/imunologia , Complexo CD3/metabolismo , Antígenos CD8/imunologia , Antígenos CD8/metabolismo , Colo/imunologia , Colo/patologia , Colo/cirurgia , Neoplasias Colorretais/genética , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/cirurgia , Intervalo Livre de Doença , Feminino , Fatores de Transcrição Forkhead/imunologia , Fatores de Transcrição Forkhead/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Reto/imunologia , Reto/patologia , Reto/cirurgia , Antígeno-1 Intracelular de Células T/imunologia , Antígeno-1 Intracelular de Células T/metabolismo
5.
Life Sci ; 254: 117773, 2020 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-32418896

RESUMO

The disturbance of the immune homeostasis caused by infection is decisive for multiple organ dysfunction caused by sepsis. Both the th17 cell and the regulatory cell(Tregs) are important components of the immune system and play a crucial role in maintaining immune homeostasis. In this study, we explored the effect of Maresin1, an emerging specific pro-inflammatory mediator, on the balance of Th17/Treg in sepsis, and investigated the underlying mechanism. We used the male C57BL/6 mice to establish the model of sepsis-induced lung injury by cecal ligation and puncture to verify the protective effect of Maresin1. Our study showed that Maresin1 could significantly inhibit the excessive inflammatory response and promote the inflammation regression in the process of sepsis-induced acute lung injury, thereby reducing lung damage and improving lung function. These effects were accompanied with the regulation of Maresin1 on the Th17/Treg balance in the early stages of sepsis. We demonstrated that Maresin1 has a certain effect on increasing the number of Treg and decreasing the number of Th17 cells in the early stages of sepsis, which is consistent with its effect on STAT3/RORγt and STAT5/Foxp3 signal pathways. Our study elucidated for the first time the relationship between Maresin1 and Th17/Treg balance in sepsis-induced acute lung injury.


Assuntos
Lesão Pulmonar Aguda/tratamento farmacológico , Lesão Pulmonar Aguda/imunologia , Ácidos Docosa-Hexaenoicos/farmacologia , Linfócitos T Reguladores/efeitos dos fármacos , Células Th17/efeitos dos fármacos , Animais , Citocinas/imunologia , Modelos Animais de Doenças , Fatores de Transcrição Forkhead/imunologia , Inflamação/tratamento farmacológico , Inflamação/imunologia , Inflamação/patologia , Pulmão/metabolismo , Pulmão/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/imunologia , Distribuição Aleatória , Fator de Transcrição STAT3/imunologia , Fator de Transcrição STAT5/imunologia , Sepse/tratamento farmacológico , Sepse/imunologia , Transdução de Sinais/efeitos dos fármacos , Linfócitos T Reguladores/imunologia , Células Th17/imunologia
6.
Cancer Immunol Immunother ; 69(9): 1917-1928, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32385519

RESUMO

Little is known about the clinical significance of the peripheral blood CD4+ CD25+ FOXP3+ regulatory T cells (Tregs) and T helper-17 (Th17) cells in lymphoma patients. In this study, the prognostic and clinical significance of peripheral blood Tregs and Th17 cells were evaluated in lymphoma patients during different phases. The frequency of Tregs and Th17 lymphocytes was measured by flow cytometry method in 47 classical Hodgkin's lymphoma (cHL) and 48 diffuse large B cell lymphoma (DLBCL) patients. Our results showed that the frequency of Tregs and absolute Treg count was significantly reduced in relapsed patients compared to patients at the remission phase, as well as with newly diagnosed untreated patients in both groups. Patients who reached complete remission had elevated frequency of CD4+ FOXP3+ lymphocytes, Tregs, absolute Treg count, Treg/CD4 and Treg/Th17 ratio in the cHL group and CD4+ CD25+ cells in DLBCL group. The frequency of Tregs, absolute Treg count and Treg/Th17 ratio in cHL patients and CD4+ FOXP3+ and CD4+ CD25+ cells in DLBCL patients positively associated with survival rate. Moreover, the percentage of Tregs and absolute Treg count positively correlated with white blood cell, platelet count and ESR level in cHL patients and with white blood cell count in DLBCL patients. The initial number of Tregs/Th17 cells and also the Treg/Th17 ratio was not associated with changes in disease-free survival (DFS) in both groups. Therefore, higher frequency of peripheral blood Tregs and Treg/Th17 ratio might be associated with a favorable outcome in lymphoma patients, better response to chemotherapy and lower rate of relapse.


Assuntos
Antígenos CD4/imunologia , Fatores de Transcrição Forkhead/imunologia , Subunidade alfa de Receptor de Interleucina-2/imunologia , Linfócitos T Reguladores/imunologia , Células Th17/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/imunologia , Adulto Jovem
7.
J Agric Food Chem ; 68(17): 4893-4902, 2020 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-32275817

RESUMO

Ginsenoside Rg3 (GRg3) is one of the major bioactive ingredients of ginseng, which is not only used as a herbal medicine but also used as a functional food to support body functions. In this study, the beneficial effects of GRg3 on rheumatoid arthritis (RA) mice was evaluated from anti-inflammatory and immunosuppressive aspects. The footpad swelling rate, pathological changes of the ankle joint, and levels of tumor necrosis factor α, interleukin 6, interleukin 10, and tumor necrosis factor ß were used to assess the anti-inflammatory effect of GRg3 on RA mice. Flow cytometric analysis of CD4+CD25+Foxp3+Treg cell percentage and metabolomic analysis based on gas chromatography-tandem mass spectrometry were used to assess the immunosuppressive effect and underlying mechanisms. GRg3 exhibited anti-inflammatory and immunosuppressive effects on RA mice. The potential mechanisms were related to regulate the pathways of oxidative phosphorylation and enhance the function of CD4+CD25+Foxp3+Treg cells to maintain peripheral immune tolerance of RA mice. These findings can provide a preliminary experimental basis to exploit GRg3 as a functional food or an effective complementary for the adjuvant therapy of RA.


Assuntos
Anti-Inflamatórios/administração & dosagem , Artrite Reumatoide/tratamento farmacológico , Ginsenosídeos/administração & dosagem , Linfócitos T Reguladores/imunologia , Animais , Artrite Reumatoide/induzido quimicamente , Artrite Reumatoide/genética , Artrite Reumatoide/imunologia , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/imunologia , Adjuvante de Freund/efeitos adversos , Humanos , Subunidade alfa de Receptor de Interleucina-2/genética , Subunidade alfa de Receptor de Interleucina-2/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Linfócitos T Reguladores/efeitos dos fármacos
8.
Eur J Immunol ; 50(7): 986-999, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32144749

RESUMO

SOCS3 is a cytosolic inhibitor of cytokine signaling that suppresses the activation of cytokine receptor-associated JAK kinases. Mechanistically, SOCS3 is recruited to a site in the cytokine receptors known as the SOCS3-interaction motif, and then binds JAK molecules to inhibit their kinase activity. The SOCS3-interaction motif is found in receptors of the gp130 cytokine family but mostly absent from other cytokine receptors, including γc. Thus, SOCS3 has been considered a selective suppressor of gp130 family cytokines, but not γc cytokines. Considering that γc signaling induces SOCS3 expression in T cells, here we revisited the role of SOCS3 on γc signaling. Using SOCS3 transgenic mice, we found that increased abundance of SOCS3 not only suppressed signaling of the gp130 family cytokine IL-6, but also signaling of the γc family cytokine IL-7. Consequently, SOCS3 transgenic mice were impaired in IL-7-dependent T cell development in the thymus and the homeostasis of mature T cells in peripheral tissues. Moreover, enforced SOCS3 expression interfered with the generation of Foxp3+ regulatory T cells that requires signaling by the γc family cytokine IL-2. Collectively, we report an underappreciated role for SOCS3 in suppressing γc cytokine signaling, effectively expanding its scope of target cytokines in T cell immunity.


Assuntos
Citocinas/imunologia , Imunidade Celular , Transdução de Sinais/imunologia , Proteína 3 Supressora da Sinalização de Citocinas/imunologia , Linfócitos T Reguladores/imunologia , Animais , Feminino , Fatores de Transcrição Forkhead/imunologia , Masculino , Camundongos , Linfócitos T Reguladores/citologia
9.
Int Arch Allergy Immunol ; 181(5): 353-356, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32160611

RESUMO

BACKGROUND: Atopic dermatitis (AD) is one of the most common inflammatory skin diseases, with an increasing incidence in clinical practice. AD models have demonstrated that TGF-ß signaling is compromised in regulatory T cells (Tregs). OBJECTIVES: This study aimed to investigate the TGF-ß-dependent in vitro conversion of CD4+CD25- T cells derived from AD-patients into CD4+CD25+Foxp3+ induced Tregs (iTregs) in comparison to healthy controls. METHODS: To analyze in vitro iTreg conversion, human CD4+CD25- T cells were cultured on anti-CD3-coated plates in the presence of TGF-ß and IL-2 for up to 3 days. Consequently, the underlying mechanism of impaired CD4+CD25+Foxp3+ iTreg generation was explored by focusing on TGF-ß signaling. Finally, the functionality of iTregs was investigated. RESULTS: Conversion of CD4+CD25-Foxp3- into CD4+CD25+Foxp3+ iTregs was diminished in AD individuals. Impaired iTreg generation was accompanied by a reduced surface expression of GARP (glycoprotein A repetitions predominant), a marker for activated Tregs. A reduced expression of Smad3 mRNA was revealed in CD4+CD25- T cells. Interestingly, the suppressive quality of iTregs was found to be equal in cells derived from AD and healthy donors. CONCLUSION: The signaling effect of TGF-ß receptors on the suppressor quality of iTreg conversion is conserved. Impaired iTreg generation might be a reason for the lack of immune suppression in AD patients and contributes to the chronicity of the disease.


Assuntos
Dermatite Atópica/imunologia , Ativação Linfocitária/imunologia , Subpopulações de Linfócitos T/imunologia , Linfócitos T Reguladores/imunologia , Adolescente , Adulto , Idoso , Antígenos CD4/imunologia , Diferenciação Celular/imunologia , Feminino , Fatores de Transcrição Forkhead/imunologia , Humanos , Técnicas In Vitro , Subunidade alfa de Receptor de Interleucina-2/imunologia , Masculino , Pessoa de Meia-Idade , Fator de Crescimento Transformador beta/imunologia , Adulto Jovem
10.
Breast Cancer Res ; 22(1): 32, 2020 03 26.
Artigo em Inglês | MEDLINE | ID: mdl-32216826

RESUMO

BACKGROUND: The immune microenvironment in ductal carcinoma in situ (DCIS) and its significance are not well established. This study was conducted to evaluate the immune microenvironment of DCIS including the composition of tumor-infiltrating lymphocyte (TIL) subsets and PD-L1+ immune cells and to compare it with that of invasive breast cancer. MATERIALS AND METHODS: A total of 671 cases including three different disease groups of pure DCIS, DCIS with microinvasion (DCIS-M), and invasive carcinoma were included in this study. CD4+, CD8+, and FOXP3+ TIL subsets and PD-L1+ immune cells were detected with immunohistochemistry using tissue microarrays and were analyzed in relation to clinicopathologic characteristics and different disease groups. RESULTS: In pure DCIS, high infiltrations of CD4+, CD8+, and FOXP3+ T cells and the presence of PD-L1+ immune cells were associated with high nuclear grade, comedo-type necrosis, hormone receptor (HR) negativity, and high Ki-67 proliferation index. All immune cell infiltrations were higher in invasive carcinoma than in pure DCIS regardless of the HR status. While CD4+ T cells were more abundant than CD8+ T cells in pure DCIS, CD8+ T cells were dominant in invasive carcinoma, especially in HR-negative tumors. Within individual cases of invasive carcinoma with DCIS component, all immune cell subset infiltration was higher in the invasive component than in the DCIS component; however, CD4+ TIL infiltration did not differ between the two components in HR-negative tumors. Comparing pure DCIS, DCIS-M, and DCIS associated with invasive carcinoma (DCIS-INV), CD4+ TIL infiltration revealed a gradual increase from pure DCIS to DCIS-M and DCIS-INV in the HR-negative group, whereas FOXP3+ TIL infiltration was significantly increased in DCIS-INV than in pure DCIS in the HR-positive group. The high infiltration of FOXP3+ TIL and the presence of PD-L1+ immune cells were associated with tumor recurrence in patients with pure DCIS. CONCLUSIONS: Our study showed that the immune microenvironment differs significantly not only between DCIS and invasive carcinoma but also between pure DCIS, DCIS-M, and DCIS-INV depending on the HR status.


Assuntos
Antígeno B7-H1/metabolismo , Biomarcadores Tumorais/imunologia , Neoplasias da Mama/imunologia , Carcinoma Intraductal não Infiltrante/imunologia , Fatores de Transcrição Forkhead/metabolismo , Linfócitos do Interstício Tumoral/imunologia , Microambiente Tumoral , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígeno B7-H1/imunologia , Neoplasias da Mama/patologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Carcinoma Intraductal não Infiltrante/patologia , Feminino , Fatores de Transcrição Forkhead/imunologia , Humanos , Pessoa de Meia-Idade , Estudos Retrospectivos
11.
J Leukoc Biol ; 107(6): 893-905, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32083339

RESUMO

TNF is a key proinflammatory and immunoregulatory cytokine whose deregulation is associated with the development of autoimmune diseases and other pathologies. Recent studies suggest that distinct functions of TNF may be associated with differential engagement of its two receptors: TNFR1 or TNFR2. In this review, we discuss the relative contributions of these receptors to pathogenesis of several diseases, with the focus on autoimmunity and neuroinflammation. In particular, we discuss the role of TNFRs in the development of regulatory T cells during neuroinflammation and recent findings concerning targeting TNFR2 with agonistic and antagonistic reagents in various murine models of autoimmune and neuroinflammatory disorders and cancer.


Assuntos
Encefalomielite Autoimune Experimental/genética , Esclerose Múltipla/genética , Neuroimunomodulação/genética , Receptores Tipo II do Fator de Necrose Tumoral/genética , Receptores Tipo I de Fatores de Necrose Tumoral/genética , Transdução de Sinais/genética , Fator de Necrose Tumoral alfa/genética , Animais , Artrite Reumatoide/genética , Artrite Reumatoide/imunologia , Artrite Reumatoide/metabolismo , Artrite Reumatoide/patologia , Autoimunidade/genética , Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/metabolismo , Encefalomielite Autoimune Experimental/patologia , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/imunologia , Regulação da Expressão Gênica , Humanos , Doenças Inflamatórias Intestinais/genética , Doenças Inflamatórias Intestinais/imunologia , Doenças Inflamatórias Intestinais/metabolismo , Doenças Inflamatórias Intestinais/patologia , Camundongos , Esclerose Múltipla/imunologia , Esclerose Múltipla/metabolismo , Esclerose Múltipla/patologia , Neoplasias/genética , Neoplasias/imunologia , Neoplasias/metabolismo , Neoplasias/patologia , Psoríase/genética , Psoríase/imunologia , Psoríase/metabolismo , Psoríase/patologia , Receptores Tipo I de Fatores de Necrose Tumoral/imunologia , Receptores Tipo II do Fator de Necrose Tumoral/imunologia , Transdução de Sinais/imunologia , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/patologia , Fator de Necrose Tumoral alfa/imunologia
12.
J Med Microbiol ; 69(4): 591-599, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32043953

RESUMO

Introduction. Staphylococcal enterotoxin B (SEB) is an extensively studied super-antigen. A previous study by us suggested that SEB exposure during pregnancy could alter the percentage of CD4+ and CD8+ T cells in the peripheral blood of neonatal offspring rats.Aim. It is unknown whether SEB exposure during pregnancy can influence the development of regulatory T cells (Tregs) in the peripheral blood of neonatal offspring rats.Methodology. Pregnant rats at gestational day 16 were intravenously injected with 15 µg SEB. Peripheral blood was acquired from neonatal offspring rats on days 1, 3 and 5 after delivery and from adult offspring rats for determination of Treg number by cytometry, cytokines by ELISA, and FoxP3 expression by real-time PCR and western blot.Results. SEB given to pregnant rats significantly increased the absolute number of Tregs and the expression levels of FoxP3, IL-10 and TGF-ß (P<0.05, P<0.01) in the peripheral blood of not only neonatal but also adult offspring rats. Furthermore, repeated SEB exposure in adult offspring rats significantly decreased the absolute number of Tregs (P<0.01), and the expression levels of FoxP3, IL-10 and TGF-ß (P<0.05, P<0.01) in their peripheral blood.Conclusion. Prenatal SEB exposure attenuates the development and function of Tregs to repeated SEB exposure in the peripheral blood of adult offspring rats.


Assuntos
Enterotoxinas/imunologia , Complicações na Gravidez/imunologia , Efeitos Tardios da Exposição Pré-Natal/imunologia , Infecções Estafilocócicas/imunologia , Linfócitos T Reguladores/imunologia , Animais , Feminino , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/imunologia , Humanos , Interleucina-10/genética , Interleucina-10/imunologia , Masculino , Exposição Materna/efeitos adversos , Gravidez , Complicações na Gravidez/microbiologia , Efeitos Tardios da Exposição Pré-Natal/genética , Efeitos Tardios da Exposição Pré-Natal/microbiologia , Ratos , Ratos Sprague-Dawley , Infecções Estafilocócicas/genética , Infecções Estafilocócicas/microbiologia , Staphylococcus aureus/genética , Staphylococcus aureus/imunologia , Linfócitos T Reguladores/citologia
13.
Ann Hematol ; 99(3): 421-429, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31984437

RESUMO

ß-thalassemia major is one of the most common hematologic disorders in the world. It causes severe anemia and patients require regular blood transfusions, which causes different complications such as iron overload and alloimmunization. Regulatory T cells (Tregs) have an important role in regulation of immune responses. FoxP3 is the major marker of Tregs and its expression can be influenced by different factors. GDF-15 is another gene that plays a role in iron homeostasis and regulation of immune system in different diseases. The aim of this study was to assess the frequency of Tregs and FoxP3/GDF-15 gene expression in ß-thalassemia major patients with and without alloantibody as well as its correlation with different factors such as serum ferritin and folate levels. This study was conducted on 68 ß-thalassemia major patients with and without alloantibodies in comparison with 20 healthy individuals with matched age and sex as control group. Enzyme-linked immunosorbent assay (ELISA), flow cytometry, and real-time PCR were performed in order to evaluate serum ferritin and folate levels, frequency of Tregs, and the expression of FoxP3 and GDF-15 genes, respectively. The percentage and absolute count of Tregs were increased in patients compared with controls (P = 0.0003), but there was no difference between responders and non-responders (P > 0.05). The Tregs count correlated positively with serum ferritin. No correlation was observed between target genes and serum ferritin and folate, but there was a positive significant correlation between the expression of FoxP3 and GDF-15 genes, which shows the immunosuppressive role of GDF-15.


Assuntos
Ferritinas , Ácido Fólico , Fatores de Transcrição Forkhead , Regulação da Expressão Gênica/imunologia , Fator 15 de Diferenciação de Crescimento , Isoanticorpos , Linfócitos T Reguladores , Talassemia beta , Adolescente , Adulto , Criança , Feminino , Ferritinas/sangue , Ferritinas/imunologia , Ácido Fólico/sangue , Ácido Fólico/imunologia , Fatores de Transcrição Forkhead/biossíntese , Fatores de Transcrição Forkhead/imunologia , Fator 15 de Diferenciação de Crescimento/biossíntese , Fator 15 de Diferenciação de Crescimento/imunologia , Humanos , Isoanticorpos/sangue , Isoanticorpos/imunologia , Masculino , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Linfócitos T Reguladores/patologia , Talassemia beta/sangue , Talassemia beta/imunologia , Talassemia beta/patologia
14.
Ann Surg ; 271(4): 693-700, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-30308614

RESUMO

OBJECTIVE: To determine whether prognostic nutritional index (PNI) affects clinical outcome through local immunity in esophageal cancers. BACKGROUND: PNI is an indicator of nutritional status and systemic immune competence, and has attracted attention as a prognostic biomarker. Tumor-infiltrating lymphocytes (TILs) are a specific histological feature of human cancers, reflecting an individual's immunological tumor response. METHODS: Using a nonbiased database of 337 curatively resected esophageal cancers, we evaluated the relationship between PNI, TILs status, CD8 expression by immunohistochemical staining, and clinical outcome. RESULTS: Compared with PNI-high cases (n = 220), PNI-low cases (n = 117) showed significantly worse overall survival (log-rank P < 0.001; hazard ratio: 2.23; 95% confidence interval: 1.56-3.18; P < 0.001; multivariate hazard ratio: 1.67; 95% confidence interval: 1.14-2.44; P = 0.008). The TILs status was also significantly correlated with overall survival (P < 0.001). In addition, PNI was significantly associated with TILs status (P < 0.001) and the CD8-positive cell count (P = 0.041). A significant relationship between the peripheral blood lymphocyte count and TILs status was also observed (P < 0.001). CONCLUSIONS: PNI and TILs score expression were associated with clinical outcome in esophageal cancer, supporting their roles as prognostic biomarkers. Considering the relationship between PNI and TILs, nutritional status and systemic immune competence may influence patient prognosis through local immune response.


Assuntos
Neoplasias Esofágicas/imunologia , Neoplasias Esofágicas/cirurgia , Linfócitos do Interstício Tumoral/imunologia , Avaliação Nutricional , Idoso , Biomarcadores Tumorais/imunologia , Antígenos CD8/imunologia , Feminino , Fatores de Transcrição Forkhead/imunologia , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Estudos Retrospectivos
15.
J Allergy Clin Immunol ; 145(1): 358-367.e2, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31600545

RESUMO

BACKGROUND: Thymic hypoplasia/aplasia occurs as a part of DiGeorge syndrome, which has several known genetic causes, and with loss-of-function mutations in forkhead box N1 (FOXN1). OBJECTIVE: We sought to determine the cause of selective T-cell lymphopenia with inverted kappa/lambda ratio in several kindreds. METHODS: Patients were identified through newborn screening for severe combined immunodeficiency using the T-cell receptor excision circle assay. Those found to have selective T-cell lymphopenia underwent testing with chromosomal microarray analysis. Three-week-old mice heterozygous for a loss-of-function mutation in forkhead box I3 (FOXI3), a candidate gene within the common deleted region found in patients, were compared with wild-type littermates. Assessments included body and organ weights, flow cytometric analysis of thymocytes and splenocytes, and histologic/transcriptomic analyses of thymic tissue. RESULTS: Five kindreds with similar immunophenotypes that included selective T-cell lymphopenia had overlapping microdeletions at chromosome 2p11.2 that spanned FOXI3 and, in most cases, the immunoglobulin kappa light chain locus. Studies in a mouse knockout strain for FOXI3 revealed smaller body weights and relatively lower thymus weights in heterozygous compared with wild-type animals. Histology and flow cytometry on spleens and thymi from 3-week-old pups for T- and B-cell subsets and epithelial cells did not show any significant qualitative or quantitative differences. Transcriptomic analysis of thymic RNA revealed divergence in global transcriptomic signatures, and Ingenuity Pathway Analysis revealed predicted dysfunction in epithelial adherens junctions. CONCLUSIONS: Microdeletions at chromosome 2p11.2 are associated with T-cell lymphopenia and probable thymic hypoplasia in human subjects, and haploinsufficiency for FOXI3, a candidate gene within the deleted region, is the likely underlying cause.


Assuntos
Deleção Cromossômica , Cromossomos Humanos Par 2/genética , Síndrome de DiGeorge/genética , Fatores de Transcrição Forkhead/genética , Mutação com Perda de Função , Animais , Cromossomos Humanos Par 2/imunologia , Síndrome de DiGeorge/imunologia , Síndrome de DiGeorge/patologia , Feminino , Fatores de Transcrição Forkhead/imunologia , Humanos , Masculino , Camundongos , Camundongos Mutantes , Timo/imunologia , Timo/patologia
16.
Hum Immunol ; 81(1): 41-47, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31735443

RESUMO

Intracranial aneurysm (IA) is a bulging of blood vessels around the brain that is often asymptomatic but may cause severe complications and death if ruptured. Macrophage-mediated immune responses can contribute to the development of IA. During homeostasis and inflammation, circulating monocytes can infiltrate the vasculature, where they develop into macrophages, and modulate immune responses. Based on the expression of CD14 and CD16, total circulating monocytes can be distinguished into three main subsets, including the CD14+CD16- classical monocytes, the CD14+CD16+ intermediate monocytes, and the CD14loCD16++ non-classical monocytes. In this study, we found that frequencies of CD14+CD16- classical monocytes were significantly lower in IA patients than in healthy controls, while the frequencies of CD14+CD16+ intermediate monocytes and CD14loCD16++ non-classical monocytes were significantly higher in IA patients than in healthy controls. The frequencies of CD14+CD16+ intermediate monocytes were further elevated in IA-ruptured patients compared to those in IA-unruptured patients. Compared to classical monocytes, intermediate monocytes and non-classical monocytes presented higher TNF-α and IL-1ß expression. When cocultured with autologous naive CD4 T cells, intermediate and non-classical monocytes preferentially promoted the expression of TBX21 and RORC over the expression of FOXP3 in CD4 T cells. Inhibition of TNF-α and IL-1ß slightly reduced TBX21 expression and markedly reduced RORC expression, and at the same time significantly increased FOXP3 expression in CD4 T cells. Overall, this study demonstrated that the monocytes were dysregulated in IA patients in a manner that favored the development of proinflammatory responses.


Assuntos
Aneurisma Roto/imunologia , Aneurisma Intracraniano/imunologia , Receptores de Lipopolissacarídeos/imunologia , Monócitos/imunologia , Receptores de IgG/imunologia , Adulto , Aneurisma Roto/patologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/patologia , Fatores de Transcrição Forkhead/imunologia , Proteínas Ligadas por GPI/imunologia , Humanos , Interleucina-1beta/imunologia , Aneurisma Intracraniano/patologia , Monócitos/patologia , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/imunologia , Fator de Necrose Tumoral alfa/imunologia
17.
Clin Exp Immunol ; 199(3): 255-262, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31386175

RESUMO

Regulatory T cells (Tregs ) are specialized in immune suppression and play a dominant role in peripheral immune tolerance. Treg  cell lineage development and function maintenance is determined by the forkhead box protein 3 (FoxP3) transcriptional factor, whose activity is fine-tuned by its post-translational modifications (PTMs) and interaction partners. In this review, we summarize current studies in the crystal structures, the PTMs and interaction partners of FoxP3 protein, and discuss how these insights may provide a roadmap for new approaches to modulate Treg  suppression, and new therapies to enhance immune tolerance in autoimmune diseases.


Assuntos
Doenças Autoimunes/imunologia , Fatores de Transcrição Forkhead/imunologia , Tolerância Imunológica/imunologia , Linfócitos T Reguladores/imunologia , Animais , Doenças Autoimunes/metabolismo , Cristalografia por Raios X , Fatores de Transcrição Forkhead/química , Fatores de Transcrição Forkhead/metabolismo , Humanos , Modelos Moleculares , Domínios Proteicos , Processamento de Proteína Pós-Traducional/imunologia , Linfócitos T Reguladores/metabolismo
18.
Transplantation ; 104(1): 39-53, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31335760

RESUMO

BACKGROUND: DBA/2J kidney allografts, but not heart allografts, are spontaneously accepted indefinitely in C57BL/6 (B6) mice, through regulatory tolerance mechanism dependent on Foxp3 cells. In contrast, B6 kidneys are rejected within a week in DBA/2J recipients. We hypothesized that the tolerogenic difference of the kidneys might be due to differences in number or function of plasmacytoid dendritic cells (pDCs), because these cells are potent inducers of Foxp3 cells. METHODS: pDCs from murine bone marrow, native kidneys, and spontaneously accepted kidney allografts were analyzed using flow cytometry and immunohistochemical staining. Naive T cells were cocultured with pDCs in specific strain combinations and analyzed for FoxP3 induction and functionality. MEK/ERK and NFκB inhibitors were used to assess the regulatory T-cell induction pathways. pDCs and T-cell cultures were adoptively transferred before heterotopic heart transplantation to assess allograft survival. RESULTS: DBA/2J pDCs were more potent in inducing Foxp3 in B6 T cells than the reverse combination, correlating with survival of the kidney allografts. Foxp3 induction by pDCs in vitro was dependent on pDC viability, immaturity, and class II MHC mismatch and blocked by MEK/ERK and NFκB inhibition. pDC-induced Foxp3 T cells suppressed proliferation of B6 T cells in vitro, and adoptive transfer into B6 recipients 2 weeks before heterotopic DBA/2J heart transplantation resulted in prolonged allograft survival. CONCLUSIONS: These data suggest that pDC-induced regulatory T cells are dependent on downstream signaling effects and on strain-dependent, MHC class II disparity with naive T cells, which may explain organ- and strain-specific differences in spontaneous tolerance.


Assuntos
Células Dendríticas/imunologia , Sobrevivência de Enxerto/imunologia , Tolerância Imunológica , Transplante de Rim/efeitos adversos , Linfócitos T Reguladores/imunologia , Transferência Adotiva , Aloenxertos/imunologia , Animais , Comunicação Celular/imunologia , Separação Celular , Modelos Animais de Doenças , Citometria de Fluxo , Fatores de Transcrição Forkhead/imunologia , Fatores de Transcrição Forkhead/metabolismo , Rejeição de Enxerto/imunologia , Transplante de Coração , Humanos , Rim/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos DBA , Linfócitos T Reguladores/metabolismo , Transplante Homólogo
19.
Eur J Immunol ; 50(3): 439-444, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31729760

RESUMO

It is well established that therapeutic impairment of Foxp3+ Treg in mice and humans favors immune rejection of solid tumors. Less explored is the impact Foxp3 allelic variants may have on tumor incidence, progression and therapy. In this work, we tested and demonstrate that the Foxp3fgfp reporter allele, found previously to either enhance or reduce Treg function in specific autoimmunity settings, confers increased anti-tumor immunity. Our conclusions stem out of the analysis of three tumor models of different tissue origin, in two murine genetic backgrounds. When compared to wild type animals, mice carrying the Foxp3fgfp allele spontaneously delay, reduce or prevent primary tumor growth, decrease metastasis growth, and potentiate the response to anti-CTLA4 monotherapy. These findings suggest allelic variances at the Foxp3 locus may serve as predictive indicators for personalized therapy and prognostics, and point at possible new therapeutic targets.


Assuntos
Fatores de Transcrição Forkhead/imunologia , Vigilância Imunológica/genética , Neoplasias Experimentais/imunologia , Alelos , Animais , Fatores de Transcrição Forkhead/genética , Vigilância Imunológica/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Linfócitos T Reguladores/imunologia
20.
Immunology ; 159(3): 344-353, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31755554

RESUMO

A reciprocal interaction exists between the gut microbiota and the immune system. Regulatory T (Treg) cells are important for controlling immune responses and for maintaining the intestinal homeostasis but their precise influence on the gut microbiota is unclear. We studied the effects of Treg cell depletion on inflammation of the intestinal mucosa and analysed the gut microbiota before and after depletion of Treg cells using the DEpletion of REGulatory T cells (DEREG) mouse model. DNA was extracted from stool samples of DEREG mice and wild-type littermates at different time-points before and after diphtheria toxin application to deplete Treg cells in DEREG mice. The V3/V4 region of the 16S rRNA gene was used for studying the gut microbiota with Illumina MiSeq paired ends sequencing. Multidimensional scaling separated the majority of gut microbiota samples from late time-points after Treg cell depletion in DEREG mice from samples of early time-points before Treg cell depletion in these mice and from gut microbiota samples of wild-type mice. Treg cell depletion in DEREG mice was accompanied by an increase in the relative abundance of the phylum Firmicutes and by intestinal inflammation in DEREG mice 20 days after Treg cell depletion, indicating that Treg cells influence the gut microbiota composition. In addition, the variables cage, breeding and experiment number were associated with differences in the gut microbiota composition and these variables should be respected in murine studies.


Assuntos
Colo/microbiologia , Firmicutes/crescimento & desenvolvimento , Fatores de Transcrição Forkhead/imunologia , Microbioma Gastrointestinal , Depleção Linfocítica , Linfócitos T Reguladores/imunologia , Animais , Cruzamento , Colite/imunologia , Colite/metabolismo , Colite/microbiologia , Colo/imunologia , Colo/metabolismo , Disbiose , Fezes/microbiologia , Feminino , Firmicutes/imunologia , Fatores de Transcrição Forkhead/metabolismo , Interações Hospedeiro-Patógeno , Abrigo para Animais , Masculino , Camundongos , Fatores Sexuais , Linfócitos T Reguladores/metabolismo , Fatores de Tempo
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