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1.
Immunity ; 52(1): 151-166.e6, 2020 01 14.
Artigo em Inglês | MEDLINE | ID: mdl-31924474

RESUMO

In addition to helper and regulatory potential, CD4+ T cells also acquire cytotoxic activity marked by granzyme B (GzmB) expression and the ability to promote rejection of established tumors. Here, we examined the molecular and cellular mechanisms underpinning the differentiation of cytotoxic CD4+ T cells following immunotherapy. CD4+ transfer into lymphodepleted animals or regulatory T (Treg) cell depletion promoted GzmB expression by tumor-infiltrating CD4+, and this was prevented by interleukin-2 (IL-2) neutralization. Transcriptional analysis revealed a polyfunctional helper and cytotoxic phenotype characterized by the expression of the transcription factors T-bet and Blimp-1. While T-bet ablation restricted interferon-γ (IFN-γ) production, loss of Blimp-1 prevented GzmB expression in response to IL-2, suggesting two independent programs required for polyfunctionality of tumor-reactive CD4+ T cells. Our findings underscore the role of Treg cells, IL-2, and Blimp-1 in controlling the differentiation of cytotoxic CD4+ T cells and offer a pathway to enhancement of anti-tumor activity through their manipulation.


Assuntos
Granzimas/imunologia , Neoplasias/imunologia , Fator 1 de Ligação ao Domínio I Regulador Positivo/metabolismo , Proteínas com Domínio T/metabolismo , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/transplante , Transferência Adotiva , Animais , Linhagem Celular Tumoral , Humanos , Interferon gama/imunologia , Interleucina-2/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Linfócitos T Reguladores/citologia , Microambiente Tumoral/imunologia
2.
Adv Exp Med Biol ; 1189: 179-210, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31758535

RESUMO

Foxp3-expressing regulatory T cells (Tregs) perform a vital function in the maintenance of immune homeostasis. A large part of Treg suppressive function is derived from their ability to control and restrict the availability of co-signal molecules to other T cells. However, Tregs themselves also depend on many of the same co-signals for their own homeostasis, making this a complex system of feedback. In this chapter, we discuss the critical role of co-signaling in Treg cell biology.


Assuntos
Transdução de Sinais , Linfócitos T Reguladores/citologia , Fatores de Transcrição Forkhead/metabolismo , Homeostase , Humanos
3.
Immunity ; 51(6): 1012-1027.e7, 2019 12 17.
Artigo em Inglês | MEDLINE | ID: mdl-31668641

RESUMO

Regulatory T (Treg) cells are critical mediators of immune tolerance whose activity depends upon T cell receptor (TCR) and mTORC1 kinase signaling, but the mechanisms that dictate functional activation of these pathways are incompletely understood. Here, we showed that amino acids license Treg cell function by priming and sustaining TCR-induced mTORC1 activity. mTORC1 activation was induced by amino acids, especially arginine and leucine, accompanied by the dynamic lysosomal localization of the mTOR and Tsc complexes. Rag and Rheb GTPases were central regulators of amino acid-dependent mTORC1 activation in effector Treg (eTreg) cells. Mice bearing RagA-RagB- or Rheb1-Rheb2-deficient Treg cells developed a fatal autoimmune disease and had reduced eTreg cell accumulation and function. RagA-RagB regulated mitochondrial and lysosomal fitness, while Rheb1-Rheb2 enforced eTreg cell suppressive gene signature. Together, these findings reveal a crucial requirement of amino acid signaling for licensing and sustaining mTORC1 activation and functional programming of Treg cells.


Assuntos
Arginina/metabolismo , Leucina/metabolismo , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Proteínas Monoméricas de Ligação ao GTP/metabolismo , Proteína Enriquecida em Homólogo de Ras do Encéfalo/metabolismo , Linfócitos T Reguladores/imunologia , Animais , Ciclo Celular , Diferenciação Celular/fisiologia , Linhagem Celular , Humanos , Tolerância Imunológica/imunologia , Ativação Linfocitária/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas Monoméricas de Ligação ao GTP/genética , Proteína Enriquecida em Homólogo de Ras do Encéfalo/genética , Receptores de Antígenos de Linfócitos T/imunologia , Linfócitos T Reguladores/citologia
4.
Zhongguo Xue Xi Chong Bing Fang Zhi Za Zhi ; 31(4): 400-403, 2019 Sep 23.
Artigo em Chinês | MEDLINE | ID: mdl-31612675

RESUMO

OBJECTIVE: To investigate the effect of Toxoplasma gondii excretory-secretory antigens (ESA) on CD4+ CD25+ Foxp3+ T (Treg) cells in mice carrying Lewis lung carcinoma, and examine the inhibitory effect of T. gondii ESA on tumor growth. METHODS: C57BL/6 mice were randomly assigned into the PBS group (n = 14) and the Lewis group (n = 34). Mice in the Lewis group were subcutaneously injected with 2 × 105 Lewis lung carcinoma cells in the right axilla, while animals in the PBS group were injected with the same volume of sterile PBS. On day 7 post-injection (D7), mice in the PBS group were further divided into the PBS2 group and the PBS2 + ESA group, of 7 mice in each group, and mice in the Lewis group were further divided into the Lewis2 group and the Lewis2 + ESA group, of 17 mice in each group. Then, mice in the PBS2 + ESA group and the Lewis2 + ESA group were intraperitoneally injected with 100 µL of ESA. The mouse spleen coefficient was calculated in each group 7 days post-injection with ESA, and the changes of Treg cell counts and the long-term tumor growth were measured in tumor-bearing mice. RESULTS: The spleen coefficient was significantly greater in the PBS2 + ESA group and the Lewis2 + ESA group than in the PBS2 (0.66% ± 0.09% vs. 0.30% ± 0.02%, P < 0.05) and Lewis2 groups (0.69% ± 0.07% vs. 0.33% ± 0.03%, P < 0.05) 7 days post-treatment with ESA, respectively, and the percentage of splenic Treg cells in splenocytes was significantly lower in the PBS2 + ESA group and the Lewis2 + ESA group than in the PBS2 (1.28% ± 0.14% vs. 2.06% ± 0.07%, P < 0.05) and Lewis2 groups (1.58% ± 0.14% vs. 2.44% ± 0.23%, P < 0.05), respectively. T. gondii ESA treatment caused a delay in tumor growth, and the tumor size was significantly smaller in the Lewis2 + ESA group than in the Lewis2 group (P < 0.05). CONCLUSIONS: T. gondii ESA may reduce the proportion of splenic Treg cells in splenocytes and inhibit tumor growth in mice carrying Lewis lung carcinoma.


Assuntos
Antígenos de Protozoários , Carcinoma Pulmonar de Lewis , Toxoplasma , Animais , Antígenos de Protozoários/farmacologia , Antígenos de Protozoários/uso terapêutico , Carcinoma Pulmonar de Lewis/tratamento farmacológico , Contagem de Células , Proliferação de Células/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Distribuição Aleatória , Baço/efeitos dos fármacos , Linfócitos T Reguladores/citologia , Toxoplasma/química , Resultado do Tratamento
5.
Zhongguo Zhong Yao Za Zhi ; 44(15): 3330-3334, 2019 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-31602891

RESUMO

Triptolide( TP) is isolated from the traditional Chinese medicine Tripterygium wilfordii,which exhibits notable immuneregulative effect. Th17 cells involve in inflammatory response and Treg cells contribute to immune tolerance. They both play an important role in immune response. Previous studies have investigated that TP induced hepatic Th17/Treg imbalance. However,the effect of TP on spleen Th17/Treg cells remains unclear. Therefore,the aim of present study was to investigate the effect of TP on Th17/Treg cells in spleen. In this study,the effect of TP on the proliferation of splenic lymphocyte was detected by cytotoxicity test in vitro. After different concentrations of TP( 2. 5,5,20,40 nmol·L~(-1)) were given to splenic lymphocyte,cytokines secreted from the supernatant of splenic lymphocyte were detected by cytometric bead array,and the expression of suppressor of cytokine signaling( SOCS) mRNA was detected by qRT-PCR. Female C57 BL/6 mice were continuously observed for 24 h after treatment of 500 µg·kg-1 TP. The effects of TP on the splenic tissue structure and the percentage of Th17/Treg cells were examined. The results showed that the IC50 of TP was19. 6 nmol·L~(-1) in spleen lymphocytes. TP inhibited the secretion of IL-2 and IL-10 and induced the expression of SOCS-1/3 mRNA in spleen lymphocytes at the dosage of 2. 5 and 5 nmol·L~(-1) after 24 h in vitro. Administration of TP at dosage of 500 µg·kg-1 had no significant spleen toxicity in vivo. TP treatment increased the percentage of Th17 cells after 12 h and inhibited the proportion of Treg cells after 12 and 24 h. In conclusion,TP reduced the secretion of IL-2 and IL-10 through SOCS-1/3 signaling pathway,thereby induced the percentage of Th17 cells and inhibited the percentage of Treg cells.


Assuntos
Diterpenos/farmacologia , Fenantrenos/farmacologia , Baço/efeitos dos fármacos , Linfócitos T Reguladores/citologia , Células Th17/citologia , Animais , Citocinas/metabolismo , Compostos de Epóxi/farmacologia , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Transdução de Sinais , Baço/citologia , Proteína 1 Supressora da Sinalização de Citocina/metabolismo , Proteína 3 Supressora da Sinalização de Citocinas/metabolismo
6.
Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi ; 35(7): 601-605, 2019 Jul.
Artigo em Chinês | MEDLINE | ID: mdl-31537244

RESUMO

Objective To determine whether regulatory T cells (Tregs) are involved in sevoflurane preconditioning-induced brain protection against cerebral ischemia/reperfusion injury. Methods C57BL/6 mice were preconditioned with sevoflurane and then subjected to the middle cerebral artery occlusion modeling. The brain infarct volume and neurological score were assessed at 48 hours after cerebral reperfusion. Meanwhile, the proportion of Tregs in the spleen was analyzed by flow cytometry. Then, CD25 neutralizing antibody was administrated by intraperitoneal injection, following with the analysis of cerebral ischemia/reperfusion injury and the proportion of Tregs in the spleen after sevoflurane preconditioning. Results Compared with a control group, sevoflurane preconditioning markedly mitigated the cerebral ischemia/reperfusion injury in the mice including the infarct volume and neurological score. In the meantime, sevoflurane preconditioning significantly increased the proportion of Tregs in the spleen at 48 hours after cerebral reperfusion. Compared with the isotype antibody group, the CD25 neutralizing antibody reversed the increase of Tregs induced by sevoflurane preconditioning at 48 hours after reperfusion, which was also associated with the reversal of sevoflurane preconditioning-induced protectetion against cerebral ischemia/reperfusion injury. Conclusion Tregs are involved in sevoflurane preconditioning-induced cerebral protection against ischemia/reperfusion injury.


Assuntos
Isquemia Encefálica/prevenção & controle , Precondicionamento Isquêmico , Traumatismo por Reperfusão/prevenção & controle , Sevoflurano/farmacologia , Linfócitos T Reguladores/citologia , Animais , Encéfalo/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL
7.
Nat Immunol ; 20(9): 1208-1219, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31384057

RESUMO

Regulatory T cells (Treg cells) deficient in the transcription factor Foxp3 lack suppressor function and manifest an effector T (Teff) cell-like phenotype. We demonstrate that Foxp3 deficiency dysregulates metabolic checkpoint kinase mammalian target of rapamycin (mTOR) complex 2 (mTORC2) signaling and gives rise to augmented aerobic glycolysis and oxidative phosphorylation. Specific deletion of the mTORC2 adaptor gene Rictor in Foxp3-deficient Treg cells ameliorated disease in a Foxo1 transcription factor-dependent manner. Rictor deficiency re-established a subset of Treg cell genetic circuits and suppressed the Teff cell-like glycolytic and respiratory programs, which contributed to immune dysregulation. Treatment of Treg cells from patients with FOXP3 deficiency with mTOR inhibitors similarly antagonized their Teff cell-like program and restored suppressive function. Thus, regulatory function can be re-established in Foxp3-deficient Treg cells by targeting their metabolic pathways, providing opportunities to restore tolerance in Treg cell disorders.


Assuntos
Reprogramação Celular/imunologia , Fatores de Transcrição Forkhead/genética , Alvo Mecanístico do Complexo 2 de Rapamicina/metabolismo , Proteína Companheira de mTOR Insensível à Rapamicina/genética , Linfócitos T Reguladores/imunologia , Animais , Células Cultivadas , Feminino , Regulação da Expressão Gênica , Glicólise/fisiologia , Humanos , Masculino , Alvo Mecanístico do Complexo 2 de Rapamicina/antagonistas & inibidores , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fosforilação Oxidativa , Transdução de Sinais , Linfócitos T Reguladores/citologia
8.
Int J Mol Sci ; 20(14)2019 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-31337116

RESUMO

Regulatory T cells (Treg) are mandatory elements in the maintenance of human pregnancy, but their de novo differentiation has not been completely exposed. HSPE1 chaperone expressing trophoblast cells may have a role in it. Trophoblast-derived extracellular vesicles (EVs), either at the feto-maternal interface or in circulation, target CD4+ T cells. We hypothesized that HSPE1-associated trophoblastic cell line (BeWo)-derived EVs are active mediators of Treg cell differentiation. We proved at first that recombinant HSPE1 promote human Treg cell differentiation in vitro. Developing a CRISPR-Cas9 based HSPE1 knockout BeWo cell line we could also demonstrate, that EV-associated HSPE1 induces Treg development. Next-generation sequencing of miRNA cargo of BeWo-EVs characterized the regulatory processes of Treg polarization. By the use of single-cell transcriptomics analysis, seven Treg cell subtypes were distinguished and we demonstrated for the first time that the expression level of HSPE1 was Treg subtype dependent, and CAPG expression is characteristic to memory phenotype of T cells. Our data indicate that HSPE1 and CAPG may be used as markers for identification of Treg subtypes. Our results suggest, that trophoblastic-derived iEVs-associated HSPE1 and miRNA cargo have an important role in Treg cell expansion in vitro and HSPE1 is a useful marker of Treg subtype characterization.


Assuntos
Comunicação Celular , Diferenciação Celular , Linfócitos T Reguladores/citologia , Linfócitos T Reguladores/metabolismo , Trofoblastos/metabolismo , Proliferação de Células , Vesículas Extracelulares/metabolismo , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Humanos , Proteoma , Proteômica/métodos , Linfócitos T Reguladores/imunologia , Transcriptoma
9.
Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi ; 35(6): 552-556, 2019 Jun.
Artigo em Chinês | MEDLINE | ID: mdl-31292060

RESUMO

Objective To investigate the effect of diabetes mellitus on lymphocytes in rheumatic heart valve tissue and its mechanism. Methods Valve tissues of 40 patients undergoing heart valve replacement were collected, including 20 patients in rheumatic heart disease group (without diabetes) and 20 patients in diabetic group (rheumatic heart disease combined with diabetes). In addition, 20 cases of valve tissue from control group were collected. HE staining was used to observe the damage of valve tissue and the area of collagen degeneration. CD4+ T cells, CD8+ T cells, B cells and plasma cells were detected by immunohistochemical staining. Flow cytometry was used to detect the proportion of regulatory T cells (Tregs) in peripheral blood. Results Compared with the rheumatic heart disease group, the damage of valve tissue in the diabetic group was further aggravated, the number of infiltrating inflammatory cells increased, and the area of collagen degeneration was enlarged. Compared with the control group, the number of T cells, CD4+ T cells, CD8+ T cells, B cells and plasma cells in valve tissue of patients with rheumatic heart disease increased significantly. Diabetes mellitus further increased the number of T cells, CD4+ T cells, B cells and plasma cells in valve tissue, but had no significant effect on CD8+ T cells. The proportion of Tregs in the peripheral blood of patients with rheumatic heart disease was significantly reduced. Diabetes mellitus could further reduce the proportion of Tregs. Conclusion The number of T cells, CD4+T cells, B cells and plasma cells in heart valves of rheumatic heart disease patients with diabetes mellitus go up significantly, and Treg ratio goes down.


Assuntos
Linfócitos B/citologia , Linfócitos T CD8-Positivos/citologia , Diabetes Mellitus/patologia , Valvas Cardíacas/citologia , Cardiopatia Reumática/complicações , Linfócitos T Reguladores/citologia , Estudos de Casos e Controles , Humanos
10.
Nihon Yakurigaku Zasshi ; 154(1): 17-22, 2019.
Artigo em Japonês | MEDLINE | ID: mdl-31308345

RESUMO

Subcutaneous immunotherapy (SCIT) is a causative treatment for allergic diseases. More recently, it has become clear that regulatory T (Treg) cells are increased by SCIT. Treg cells are generally divided into two main groups: 1) CD25+ Foxp3+ CD4+ T cells (Foxp3+ Treg cells) and 2) IL-10-producing Foxp3- CD4+ T cells (Tr1 cells). We demonstrated that the number of Tr1 cells in peripheral blood mononuclear cells in SCIT-treated pollinosis patients were significantly higher than that in non-SCIT-treated patients, but Foxp3+ Treg cells were not. Consistent with the results of human peripheral blood, Tr1 cells were increased in the lungs of asthmatic mice by SCIT, but Foxp3+ Treg cells were not. Moreover, in vitro-induced Tr1 cells were responded to the antigen to produce a large amount of IL-10 in in vitro and in vivo. Adoptive transfer of the induced Tr1 cells significantly suppressed the development of asthma. In any species of human and mouse, the increase in Tr1 cells rather than Foxp3+ Treg cells could be important for the effects of SCIT. The increased Tr1 cells by SCIT functionally suppressed allergic asthma probably via production of IL-10 in response to the specific antigen. Therefore, analyses of the induction mechanisms of Tr1 cells and search for compounds which induce Tr1 cells are thought to lead to development of more efficient SCIT.


Assuntos
Hipersensibilidade/terapia , Imunoterapia , Linfócitos T Reguladores/citologia , Animais , Fatores de Transcrição Forkhead , Humanos , Hipersensibilidade/imunologia , Leucócitos Mononucleares , Camundongos
11.
Nat Commun ; 10(1): 2924, 2019 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-31266950

RESUMO

Fas induces apoptosis in activated T cell to maintain immune homeostasis, but the effects of non-apoptotic Fas signaling on T cells remain unclear. Here we show that Fas promotes TH9 cell differentiation by activating NF-κB via Ca2+-dependent PKC-ß activation. In addition, PKC-ß also phosphorylates p38 to inactivate NFAT1 and reduce NFAT1-NF-κB synergy to promote the Fas-induced TH9 transcription program. Fas ligation exacerbates inflammatory bowel disease by increasing TH9 cell differentiation, and promotes antitumor activity in p38 inhibitor-treated TH9 cells. Furthermore, low-dose p38 inhibitor suppresses tumor growth without inducing systemic adverse effects. In patients with tumor, relatively high TH9 cell numbers are associated with good prognosis. Our study thus implicates Fas in CD4+ T cells as a target for inflammatory bowel disease therapy. Furthermore, simultaneous Fas ligation and low-dose p38 inhibition may be an effective approach for TH9 cell induction and cancer therapy.


Assuntos
Diferenciação Celular , Doenças Inflamatórias Intestinais/imunologia , Transdução de Sinais , Linfócitos T Reguladores/citologia , Receptor fas/imunologia , Animais , Citocinas/genética , Citocinas/imunologia , Feminino , Humanos , Doenças Inflamatórias Intestinais/genética , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Nus , NF-kappa B/genética , NF-kappa B/imunologia , Fatores de Transcrição NFATC/genética , Fatores de Transcrição NFATC/imunologia , Neoplasias/genética , Neoplasias/imunologia , Neoplasias/terapia , Proteína Quinase C beta/genética , Proteína Quinase C beta/imunologia , Linfócitos T Reguladores/imunologia , Receptor fas/genética , Proteínas Quinases p38 Ativadas por Mitógeno/genética , Proteínas Quinases p38 Ativadas por Mitógeno/imunologia
12.
Molecules ; 24(13)2019 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-31284478

RESUMO

Dihydroartemisinin (DHA) is a derivative of the herb Artemisia annua L. that has prominent immunomodulatory activity; however, its underlying mechanism remains elusive. Inflammatory bowel disease (IBD) is an idiopathic inflammatory condition characterized as an autoimmune disorder that includes dysfunctions in the T helper (Th)/T regulatory cell (Treg) balance, which normally plays pivotal roles in immune homeostasis. The aim of this study was to explore the potential of DHA to ameliorate IBD by restoring the Th/Treg cell balance. To this end, we established mouse models of colitis induced by oxazolone (OXA) and 2,4,6-trinitro-benzene sulfonic acid (TNBS). We then treated mice with DHA at 4, 8, or 16 mg/kg/day. DHA treatment ameliorated colitis signs and reduced lymphocyte infiltration and tissue fibrosis. Moreover, DHA decreased the numbers of Th1 and Th17 cells and Th9 and Th22 cells in TNBS- or OXA-induced colitis, respectively, and increased Tregs in both models. DHA (0.8 mg/mL) also inhibited activated CD4+ T lymphocytes, which was accompanied by apoptosis induction. Moreover, it promoted heme oxygenase-1 (HO-1) production in vitro and in vivo, concomitant with CD4+ T cell apoptosis and restoration of the Th/Treg balance, and these effects were blocked by treatment with the HO-1 inhibitor Sn-protoporphyrin IX. Overall, these results suggest that DHA is a novel and valuable candidate for IBD therapy or Th/Treg immunoregulation.


Assuntos
Apoptose , Artemisininas/uso terapêutico , Heme Oxigenase-1/biossíntese , Doenças Inflamatórias Intestinais/tratamento farmacológico , Doenças Inflamatórias Intestinais/imunologia , Ativação Linfocitária/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Linfócitos T Reguladores/imunologia , Animais , Apoptose/efeitos dos fármacos , Artemisininas/farmacologia , Colite/induzido quimicamente , Colite/tratamento farmacológico , Colite/imunologia , Modelos Animais de Doenças , Indução Enzimática/efeitos dos fármacos , Doenças Inflamatórias Intestinais/enzimologia , Ativação Linfocitária/efeitos dos fármacos , Subpopulações de Linfócitos/efeitos dos fármacos , Subpopulações de Linfócitos/imunologia , Camundongos , Oxazolona , Linfócitos T Auxiliares-Indutores/citologia , Linfócitos T Auxiliares-Indutores/efeitos dos fármacos , Linfócitos T Reguladores/citologia , Linfócitos T Reguladores/efeitos dos fármacos , Ácido Trinitrobenzenossulfônico
13.
Egypt J Immunol ; 26(1): 15-29, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31332993

RESUMO

Cow's milk allergy (CMA) is known to be either IgE- or non-IgE mediated. Regulatory T (Treg) cell defect is involved in the pathogenesis of both types. Vitamin D has been suggested to improve the generation of allergen-specific Treg cell populations with the potential to provide safe and long-term alleviation of disease symptoms. This study aimed to assess Vitamin D status in children with physician-diagnosed CMA and to investigate the effect of in vitro cultivation with Vitamin D on the percentage of antigen-driven CD4+CD25highFoxp3+IL10+ Treg cells following in vitro stimulation of cells with cow's milk allergen in culture. This cross-sectional study included 20 children with CMA and 20 healthy age and sex-matched children as a control group. All patients were subjected to clinical evaluation, cow's milk skin prick test (SPT), cow's milk elimination and oral re-challenge test in patients with negative cow's milk SPT and in those with gastrointestinal presentation, measurement of serum Vitamin D level and assessment of the percentage of antigen-driven CD4+CD25highFoxp3+IL10+ Treg cells in response to stimulation with cow's milk allergen extract with and without Vitamin D in culture. Vitamin D deficiency was detected in 80% of children with CMA. Percentage of Foxp3+ and IL10+ co-expression on Treg cells was significantly increased after stimulation with cow's milk allergen extract in the presence of Vitamin D. A significant positive correlation was observed between serum Vitamin D level and percentage of antigen-driven CD4+CD25highFoxp3+IL10+ Treg cells as well as level of Foxp3+ and IL10+ co-expression on Treg cells at baseline (control cultures without stimulation) and after PBMCs stimulation with cow's milk allergen extract in the presence of Vitamin D. Re-stimulation with cow's milk allergen extract was performed in vitro in order to evaluate milk-induced immune stimulation and regulation. In conclusion, patients with CMA whether IgE- or non-IgE mediated had Vitamin D deficiency with a decreased number of CD4+CD25highFoxp3+IL10+ Treg cells which increased after in vitro addition of Vitamin D with increased Foxp3 and IL10 co-expression.


Assuntos
Interleucina-10/metabolismo , Hipersensibilidade a Leite/imunologia , Linfócitos T Reguladores/citologia , Vitamina D/farmacologia , Animais , Bovinos , Células Cultivadas , Criança , Estudos Transversais , Fatores de Transcrição Forkhead/metabolismo , Humanos , Lactente
14.
Egypt J Immunol ; 26(1): 129-139, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31333003

RESUMO

T regulatory cells (Tregs) are a cornerstone regulator for immune responses and inflammatory reactions. Abnormal number or function of Tregs causes deranged immune response that increases the autoimmune disorders and inflammatory conditions. Type 1 diabetes mellitus is an autoimmune disease associated with many complications, of which, Cardiovascular complications are fundamental and responsible for profound morbidity and mortality. Understanding the immunopathogenesis of these disorders allows early diagnosis and better management by innovating new therapeutic targets. In this study, we aimed to detect the association between CD4+CD8+FOX3+ Tregs, T1DM, and associated cardiovascular complications. The study included 144 individuals divided into three groups, group 1 included 48 patients suffering from T1DM without cardiovascular complications, group II: included 48 type T1DM patients with cardiovascular complications. Group III: included 48 healthy control subjects. For all participants, markers for inflammation, and cardiovascular involvement were assessed. The percentage of CD4+ CD25+ FOXP3+ Regulatory T- cells (Tregs) was measured by flow cytometry using peripheral blood samples. The level of Treg was lowest in group II and highest in group III, the difference was highly significant P < 0.001. Treg in group I significantly correlated with age (r= 0.58, P=0.004), CK-mb (r= 0.61, P=0.04) and LDL (r= -.61, P=0.4). While in group II, it correlated with triglyceride level, (r= 0.65 and a P =- 0.02). In conclusion, Lower levels of Tregs are associated with cardiovascular complications in TIDM patients.


Assuntos
Doenças Cardiovasculares/complicações , Diabetes Mellitus Tipo 1/complicações , Linfócitos T Reguladores/citologia , Biomarcadores , Estudos de Casos e Controles , Diabetes Mellitus Tipo 1/imunologia , Citometria de Fluxo , Fatores de Transcrição Forkhead/metabolismo , Humanos , Subunidade alfa de Receptor de Interleucina-2
15.
Monoclon Antib Immunodiagn Immunother ; 38(3): 114-119, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31192779

RESUMO

The establishment of a relevant regulatory T cell (Treg) pool in the periphery is of importance to ensure immune homoeostasis. Finely tuned signaling pathways in Tregs control the immune response during extreme endocrine changes in pregnancy and afterward. In this study, we investigate the population of Tregs and, in particular, the natural Tregs (nTregs) in healthy women divided into three groups according to the number of previous pregnancies, if any (Gr.1-one pregnancy, Gr.2-≥2 pregnancies, and Gr.0-no pregnancy). The overall analysis showed similar proportions in the entire Treg pool and nTregs (FoxP3+CD45RA+) in all the three groups (p > 0.05). However, the age-related trend of CD25+ nTregs was found to be different in parous and nonparous women. Analysis of phosphorylated ERK1/2, an important signaling molecule in T cell maintenance, showed a significantly higher percentage in CD25+ nTregs in the group of nonparous compared with parous women (p < 0.05). Thus, our results provide evidence that pregnancy may exert a long-lasting impact on the subset of nTregs due to the extreme changes in the hormonal status, which in turn, influences pre- and post-thymic maturation.


Assuntos
Subunidade alfa de Receptor de Interleucina-2/metabolismo , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Paridade , Linfócitos T Reguladores/imunologia , Adulto , Diferenciação Celular , Feminino , Humanos , Subunidade alfa de Receptor de Interleucina-2/imunologia , Proteína Quinase 1 Ativada por Mitógeno/imunologia , Proteína Quinase 3 Ativada por Mitógeno/imunologia , Gravidez , Linfócitos T Reguladores/citologia , Linfócitos T Reguladores/metabolismo , Adulto Jovem
16.
Medicine (Baltimore) ; 98(24): e15952, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31192933

RESUMO

This study aims at analyzing the Th17/Treg cell level and clinical characteristics of the peripheral blood of patients with Sjogren's syndrome (SS) complicated with primary biliary cirrhosis (PBC) so as to deepen the understanding of this disease and seek for its possible onset mechanism.A retrospective analysis was conducted on the clinical data of 24 patients [8 (33%) males and 16 (67%) females] with SS complicated with primary biliary cirrhosis, 50 patients with primary SS and 93 healthy volunteers. These patients were divided into 3 groups: experimental group (SS+PBC), control group (SS) and healthy group. Then, peripheral blood was collected and flow cytometry was conducted to detect level of Th17 cells and Treg cells. A fully automatic biochemical detector was used to detect the corresponding liver function index. The correlation analysis was made based on the clinical manifestations and biochemical characteristics.Compared with the healthy group and control group, the experimental group had the highest Th17/Treg cell ratio, and Th17 cell frequency was significantly increased (P <.05). Furthermore, ALT, AST, ALP, γ-GT, TBIL, and other indexes were positively correlated to the Th17/Treg ratio (P <.05).Th17/Treg cell level and its ratio in peripheral blood of patients with SS complicated with primary biliary cirrhosis were significantly unbalanced, indicating that Th17 cells participate in the onset of this disease to a large extent. Furthermore, the Th17/Treg ratio has a certain correlation with some of the liver function indexes, on which a stratified analysis could be made furtherly according to the seriousness of the conditions.


Assuntos
Cirrose Hepática Biliar/sangue , Síndrome de Sjogren/sangue , Linfócitos T Reguladores/citologia , Células Th17/citologia , Adulto , Idoso , Biomarcadores/metabolismo , Estudos de Casos e Controles , Feminino , Citometria de Fluxo , Humanos , Fígado/metabolismo , Cirrose Hepática Biliar/metabolismo , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Síndrome de Sjogren/complicações , Síndrome de Sjogren/metabolismo
17.
Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi ; 35(4): 296-301, 2019 Apr.
Artigo em Chinês | MEDLINE | ID: mdl-31167687

RESUMO

Objective To investigate the role of CD161+ regulatory T cells (Treg) in reducing valve injury in rheumatic heart disease rats and the underlying mechanism. Methods CD161- and CD161+ regulatory T cells (Tregs) were separated by flow cytometry and then cultured. The concentrations of interleukin 10 (IL-10) and transforming growth factor ß (TGF-ß) in the supernates were detected by ELISA. Rat models of rheumatic heart disease were established by mixing A type hemolytic streptococcus suspension with Freund's complete adjuvant. They were divided into control group, CD161-Treg group and CD161+Treg group. One week later, heart blood and mitral valve were taken from the model rats. The proportion of follicular helper T (Tfh) cells, B cells and plasma cells was detected by flow cytometry. Histopathological changes were detected by HE staining and the number of B cells and plasma cells by immunohistochemical staining. ELISA was used to detect the level of IL-21 in serum. Results The ability of CD161+Tregs to secrete IL-10 and TGF-ß was significantly higher than that of CD161-Tregs. Compared with the rats injected with CD161-Tregs, CD161+Tregs could significantly reduce the damage of valve tissue and the proportion of B cells and plasma cells in valve tissue. Moreover, CD161+Tregs injection could reduce the proportion of Tfh cells, B cells and plasma cells in rat blood and decrease the content of IL-21 in serum. Conclusion CD161+Tregs can reduce the valve injury of rheumatic heart disease by inhibiting the proliferation and differentiation of Tfh cells and B cells.


Assuntos
Valvas Cardíacas/patologia , Cardiopatia Reumática/imunologia , Linfócitos T Reguladores/citologia , Animais , Linfócitos B/citologia , Interleucina-10/metabolismo , Interleucinas/sangue , Subfamília B de Receptores Semelhantes a Lectina de Células NK , Plasmócitos/citologia , Ratos , Fator de Crescimento Transformador beta/metabolismo
18.
Immunohorizons ; 3(2): 71-87, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-31236543

RESUMO

We previously reported that neuroimmune semaphorin (Sema) 4A regulates the severity of experimental allergic asthma and increases regulatory T (Treg) cell numbers in vivo; however, the mechanisms of Sema4A action remain unknown. It was also reported that Sema4A controls murine Treg cell function and survival acting through neuropilin 1 (NRP-1) receptor. To clarify Sema4A action on human T cells, we employed T cell lines (HuT78 and HuT102), human PBMCs, and CD4+ T cells in phenotypic and functional assays. We found that HuT78 demonstrated a T effector-like phenotype (CD4+CD25lowFoxp3-), whereas HuT102 expressed a Treg-like phenotype (CD4+CD25hi Foxp3+). Neither cell line expressed NRP-1. HuT102 cells expressed Sema4A counter receptor Plexin B1, whereas HuT78 cells were Sema4A+. All human peripheral blood CD4+ T cells, including Treg cells, expressed PlexinB1 and lacked both NRP-1 and -2. However, NRP-1 and Sema4A were detected on CD3negativeCD4intermediate human monocytes. Culture of HuT cells with soluble Sema4A led to an upregulation of CD25 and Foxp3 markers on HuT102 cells. Addition of Sema4A increased the relative numbers of CD4+CD25+Foxp3+ cells in PBMCs and CD4+ T cells, which were NRP-1negative but PlexinB1+, suggesting the role of this receptor in Treg cell stability. The inclusion of anti-PlexinB1 blocking Ab in cultures before recombinant Sema4A addition significantly decreased Treg cell numbers as compared with cultures with recombinant Sema4A alone. Sema4A was as effective as TGF-ß in inducible Treg cell induction from CD4+CD25depleted cells but did not enhance Treg cell suppressive activity in vitro. These results suggest strategies for the development of new Sema4A-based therapeutic measures to combat allergic inflammatory diseases. ImmunoHorizons, 2019, 3: 71-87.


Assuntos
Proteínas do Tecido Nervoso/metabolismo , Receptores de Superfície Celular/metabolismo , Semaforinas/metabolismo , Semaforinas/farmacologia , Linfócitos T Reguladores/citologia , Linfócitos T Reguladores/metabolismo , Anticorpos , Asma/imunologia , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Fatores de Transcrição Forkhead/metabolismo , Humanos , Interleucina-2/metabolismo , Subunidade alfa de Receptor de Interleucina-2/metabolismo , Proteínas do Tecido Nervoso/imunologia , Neuropilina-1/metabolismo , Fenótipo , Receptores de Superfície Celular/imunologia , Fator de Crescimento Transformador beta/metabolismo
19.
Nat Immunol ; 20(8): 1046-1058, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31209405

RESUMO

The neonatal thymus generates Foxp3+ regulatory T (tTreg) cells that are critical in controlling immune homeostasis and preventing multiorgan autoimmunity. The role of antigen specificity on neonatal tTreg cell selection is unresolved. Here we identify 17 self-peptides recognized by neonatal tTreg cells, and reveal ligand specificity patterns that include self-antigens presented in an age- and inflammation-dependent manner. Fate-mapping studies of neonatal peptidyl arginine deiminase type IV (Padi4)-specific thymocytes reveal disparate fate choices. Neonatal thymocytes expressing T cell receptors that engage IAb-Padi4 with moderate dwell times within a conventional docking orientation are exported as tTreg cells. In contrast, Padi4-specific T cell receptors with short dwell times are expressed on CD4+ T cells, while long dwell times induce negative selection. Temporally, Padi4-specific thymocytes are subject to a developmental stage-specific change in negative selection, which precludes tTreg cell development. Thus, a temporal switch in negative selection and ligand binding kinetics constrains the neonatal tTreg selection window.


Assuntos
Autoantígenos/imunologia , Receptores de Antígenos de Linfócitos T alfa-beta/imunologia , Tolerância a Antígenos Próprios/imunologia , Linfócitos T Reguladores/citologia , Animais , Autoimunidade/imunologia , Diferenciação Celular/imunologia , Linhagem Celular , Feminino , Fatores de Transcrição Forkhead/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Desiminases de Arginina em Proteínas/metabolismo , Linfócitos T Reguladores/imunologia , Timo/citologia
20.
Mol Med Rep ; 19(6): 5377-5385, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31059096

RESUMO

Hyperglycemia promotes the growth and reproduction of bacteria, thereby increasing the probability of infection, which also causes rebound hyperglycemia. Therefore, the interactions of infection and hyperglycemia lead to the progression and deterioration of these diseases. Type 1 diabetes mellitus (T1DM) is an autoimmune disease. Studies have shown that regulatory T cells (Tregs) play a key role in maintaining islet­specific tolerance. Treg deficiency may lead to the development of early pancreatitis and T1DM, and sufficient amounts of Tregs can restore this tolerance, thereby inhibiting the occurrence of T1DM. Moreover, different subpopulations of dendritic cells (DCs) play an important role in activating autoreactive T cells and inducing autoimmune tolerance to autoantigens, which are closely related to the functional diversity caused by different phenotypes, maturation status, and the immune microenvironment of DC subpopulations. In the present study, we used streptozotocin­induced hyperglycemic mice to model T1DM and induced a Salmonella infection in the mouse model, leading to aggravated inflammation, which resulted in an elevated proportion of CD103+CD11b+ DCs and a significantly elevated proportion of CD4+FoxP3+ Tregs in the intestinal lamina propria. After co­culturing CD4+ T cells and DCs, we found that CD103+CD11b+ DCs could significantly promote the proliferation of CD4+ T cells. The elevated proportions of CD4+FoxP3+ Tregs were considered to be correlated with the increased number of CD103+CD11b+ DCs.


Assuntos
Infecções por Salmonella/patologia , Linfócitos T Reguladores/metabolismo , Animais , Antígenos CD/metabolismo , Antígeno CD11b/metabolismo , Linfócitos T CD4-Positivos/citologia , Linfócitos T CD4-Positivos/metabolismo , Técnicas de Cocultura , Citocinas/sangue , Células Dendríticas/citologia , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/imunologia , Diabetes Mellitus Experimental/patologia , Modelos Animais de Doenças , Feminino , Fatores de Transcrição Forkhead/metabolismo , Inflamação , Cadeias alfa de Integrinas/metabolismo , Mucosa Intestinal/metabolismo , Mucosa Intestinal/microbiologia , Mucosa Intestinal/patologia , Ativação Linfocitária , Camundongos , Camundongos Endogâmicos C57BL , Pâncreas/patologia , Salmonella/patogenicidade , Infecções por Salmonella/imunologia , Linfócitos T Reguladores/citologia , Linfócitos T Reguladores/imunologia
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