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1.
Proc Natl Acad Sci U S A ; 117(36): 22367-22377, 2020 09 08.
Artigo em Inglês | MEDLINE | ID: mdl-32848068

RESUMO

The γδ T cells reside predominantly at barrier sites and play essential roles in immune protection against infection and cancer. Despite recent advances in the development of γδ T cell immunotherapy, our understanding of the basic biology of these cells, including how their numbers are regulated in vivo, remains poor. This is particularly true for tissue-resident γδ T cells. We have identified the ß2 family of integrins as regulators of γδ T cells. ß2-integrin-deficient mice displayed a striking increase in numbers of IL-17-producing Vγ6Vδ1+ γδ T cells in the lungs, uterus, and circulation. Thymic development of this population was normal. However, single-cell RNA sequencing revealed the enrichment of genes associated with T cell survival and proliferation specifically in ß2-integrin-deficient IL-17+ cells compared to their wild-type counterparts. Indeed, ß2-integrin-deficient Vγ6+ cells from the lungs showed reduced apoptosis ex vivo, suggesting that increased survival contributes to the accumulation of these cells in ß2-integrin-deficient tissues. Furthermore, our data revealed an unexpected role for ß2 integrins in promoting the thymic development of the IFNγ-producing CD27+ Vγ4+ γδ T cell subset. Together, our data reveal that ß2 integrins are important regulators of γδ T cell homeostasis, inhibiting the survival of IL-17-producing Vγ6Vδ1+ cells and promoting the thymic development of the IFNγ-producing Vγ4+ subset. Our study introduces unprecedented mechanisms of control for γδ T cell subsets.


Assuntos
Antígenos CD18 , Linfócitos Intraepiteliais , Timo , Animais , Antígenos CD18/genética , Antígenos CD18/imunologia , Antígenos CD18/metabolismo , Homeostase/imunologia , Interleucina-17/genética , Interleucina-17/imunologia , Interleucina-17/metabolismo , Linfócitos Intraepiteliais/imunologia , Linfócitos Intraepiteliais/metabolismo , Linfócitos Intraepiteliais/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Timo/crescimento & desenvolvimento , Timo/imunologia , Timo/metabolismo
2.
Ecotoxicol Environ Saf ; 200: 110715, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32450432

RESUMO

Copper (Cu) is a necessary trace mineral due to its biological activity. Excessive Cu can induce inflammatory response in humans and animals, but the underlying mechanism is still unknown. Here, 240 broilers were used to study the effects of excessive Cu on oxidative stress and NF-κB-mediated inflammatory responses in immune organs. Chickens were fed with diet containing different concentrations of Cu (11, 110, 220, and 330 mg of Cu/kg dry matter). The experiment lasted for 49 days. Spleen, thymus, and bursa of Fabricius (BF) on day 49 were collected for histopathological observation and assessment of oxidative stress status. Additionally, the mRNA and protein levels of NF-κB and inflammatory cytokines were also analyzed. The results indicated that excess Cu could increase the number and area of splenic corpuscle as well as the ratio of cortex and medulla in thymus and BF. Furthermore, excessive Cu intake could decrease activities of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px); but increase contents of malondialdehyde (MDA), TNF-α, IL-1, IL-1ß; up-regulate mRNA levels of TNF-α, IFN-γ, IL-1, IL-1ß, IL-2, iNOS, COX-2, NF-κB and protein levels of TNF-α, IFN-γ, NF-κB, p-NF-κB in immune organs. In conclusion, excessive Cu could cause pathologic changes and induce oxidative stress with triggered NF-κB pathway, and might further regulate the inflammatory response in immune organs of chicken.


Assuntos
Galinhas/imunologia , Cobre/toxicidade , NF-kappa B/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Animais , Bolsa de Fabricius/enzimologia , Bolsa de Fabricius/imunologia , Bolsa de Fabricius/metabolismo , Bolsa de Fabricius/patologia , Catalase/metabolismo , Galinhas/genética , Galinhas/metabolismo , Citocinas/genética , Citocinas/metabolismo , Glutationa Peroxidase/metabolismo , Inflamação/genética , Inflamação/metabolismo , Malondialdeído/metabolismo , NF-kappa B/genética , Baço/enzimologia , Baço/imunologia , Baço/metabolismo , Baço/patologia , Superóxido Dismutase/metabolismo , Timo/enzimologia , Timo/imunologia , Timo/metabolismo , Timo/patologia
3.
Nat Commun ; 11(1): 2198, 2020 05 04.
Artigo em Inglês | MEDLINE | ID: mdl-32366944

RESUMO

The thymus supports multiple αß T cell lineages that are functionally distinct, but mechanisms that control this multifaceted development are poorly understood. Here we examine medullary thymic epithelial cell (mTEC) heterogeneity and its influence on CD1d-restricted iNKT cells. We find three distinct mTEClow subsets distinguished by surface, intracellular and secreted molecules, and identify LTßR as a cell-autonomous controller of their development. Importantly, this mTEC heterogeneity enables the thymus to differentially control iNKT sublineages possessing distinct effector properties. mTEC expression of LTßR is essential for the development thymic tuft cells which regulate NKT2 via IL-25, while LTßR controls CD104+CCL21+ mTEClow that are capable of IL-15-transpresentation for regulating NKT1 and NKT17. Finally, mTECs regulate both iNKT-mediated activation of thymic dendritic cells, and iNKT availability in extrathymic sites. In conclusion, mTEC specialization controls intrathymic iNKT cell development and function, and determines iNKT pool size in peripheral tissues.


Assuntos
Diferenciação Celular/imunologia , Células Epiteliais/imunologia , Células T Matadoras Naturais/imunologia , Timócitos/imunologia , Timo/imunologia , Animais , Antígenos CD1d/genética , Antígenos CD1d/imunologia , Antígenos CD1d/metabolismo , Diferenciação Celular/genética , Linhagem da Célula/genética , Linhagem da Célula/imunologia , Proliferação de Células/genética , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Células Epiteliais/citologia , Células Epiteliais/metabolismo , Regulação da Expressão Gênica/imunologia , Ativação Linfocitária/imunologia , Receptor beta de Linfotoxina/genética , Receptor beta de Linfotoxina/imunologia , Receptor beta de Linfotoxina/metabolismo , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Células T Matadoras Naturais/citologia , Células T Matadoras Naturais/metabolismo , Transdução de Sinais/genética , Transdução de Sinais/imunologia , Linfócitos T/citologia , Linfócitos T/imunologia , Linfócitos T/metabolismo , Timócitos/citologia , Timócitos/metabolismo , Timo/citologia , Timo/metabolismo
4.
Am J Physiol Endocrinol Metab ; 318(5): E646-E654, 2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-32125882

RESUMO

Mouse models with lifelong inactivation of estrogen receptor-α (ERα) show that ERα is the main mediator of estrogenic effects in bone, thymus, uterus, and fat. However, ERα inactivation early in life may cause developmental effects that confound the adult phenotypes. To address the specific role of adult ERα expression for estrogenic effects in bone and other nonskeletal tissues, we established a tamoxifen-inducible ERα-inactivated model by crossing CAGG-Cre-ER and ERαflox/flox mice. Tamoxifen-induced ERα inactivation after sexual maturation substantially reduced ERα mRNA levels in cortical bone, trabecular bone, thymus, uterus, gonadal fat, and hypothalamus, in CAGG-Cre-ERαflox/flox (inducible ERαKO) compared with ERαflox/flox (control) mice. 17ß-estradiol (E2) treatment increased trabecular bone volume fraction (BV/TV), cortical bone area, and uterine weight, while it reduced thymus weight and fat mass in ovariectomized control mice. The estrogenic responses were substantially reduced in inducible ERαKO mice compared with control mice on BV/TV (-67%), uterine weight (-94%), thymus weight (-70%), and gonadal fat mass (-94%). In contrast, the estrogenic response on cortical bone area was unaffected in inducible ERαKO compared with control mice. In conclusion, using an inducible ERαKO model, not confounded by lack of ERα during development, we demonstrate that ERα expression in sexually mature female mice is required for normal E2 responses in most, but not all, tissues. The finding that cortical, but not trabecular bone, responds normally to E2 treatment in inducible ERαKO mice strengthens the idea of cortical and trabecular bone being regulated by estrogen via different mechanisms.


Assuntos
Densidade Óssea/efeitos dos fármacos , Osso e Ossos/efeitos dos fármacos , Estradiol/farmacologia , Receptor alfa de Estrogênio/metabolismo , Útero/efeitos dos fármacos , Animais , Osso e Ossos/metabolismo , Receptor alfa de Estrogênio/genética , Feminino , Camundongos , Camundongos Transgênicos , Tamanho do Órgão/efeitos dos fármacos , Ovariectomia , Timo/efeitos dos fármacos , Timo/metabolismo , Útero/metabolismo
5.
PLoS One ; 15(3): e0230668, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32208448

RESUMO

The maintenance and propagation of complex mixtures of cells in vitro in the form of native organs or engineered organoids has contributed to understanding mechanisms of cell and organ development and function which can be translated into therapeutic benefits. For example, allogeneic cultured postnatal human thymus tissue has been shown to support production of naïve recipient T cells when transplanted into patients with complete DiGeorge anomaly and other genetic defects that result in congenital lack of a thymus. Patients receiving such transplants typically exhibit reversal of their immunodeficiency and normalization of their peripheral blood T cell receptor V-beta repertoire, with long-term survival. This study was designed to assess the histopathologic changes that occur in postnatal human thymus slices when cultured according to protocols used for transplanted tissues. Results showed that as thymic organ cultures progressed from days 0 through 21, slices developed increasing amounts of necrosis, increasing condensation of thymic epithelium, and decreasing numbers of residual T cells. The architecture of the thymic epithelial network remained generally well-preserved throughout the 21 days of culture, with focal expression of cytokeratin 14, a putative biomarker of thymic epithelial cells with long-term organ-repopulating potential. All organ slices derived from the same donor thymus closely resembled one another, with minor differences in size, shape, and relative content of cortex versus medulla. Similarly, slices derived from different donors showed similar histopathologic characteristics when examined at the same culture time point. Taken together, these results demonstrate that diagnostic criteria based on structural features of the tissue identifiable via hematoxylin and eosin staining and cytokeratin immunohistochemistry can be used to evaluate the quality of slices transplanted into patients with congenital athymia.


Assuntos
Timo/patologia , Células Epiteliais/citologia , Células Epiteliais/metabolismo , Humanos , Hospedeiro Imunocomprometido , Lactente , Queratina-14/metabolismo , Técnicas de Cultura de Órgãos , Linfócitos T/citologia , Linfócitos T/patologia , Timo/metabolismo , Fatores de Tempo
6.
Lupus ; 29(3): 290-302, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32041506

RESUMO

BACKGROUND: The immune system is one of the most complex regulatory systems in the body and is essential for the maintenance of homeostasis. Despite recent breakthroughs in immunology, the regulation of the immune system and the etiology of autoimmune diseases such as lupus remain unclear. Systemic lupus erythematosus is a systemic autoimmune disease with abnormally and inconsistently expressed pro-inflammatory cytokines. Pyroptosis is a pro-inflammatory form of programmed cell death that is associated with systemic lupus erythematosus. The thymus and spleen are important immune organs involved in systemic lupus erythematosus. Therefore, this study investigated the difference in expression of pyroptosis-inducing pro-inflammatory cytokines between the spleen and thymus in lupus model mice and in control mice, to describe immune regulation at the organ level. OBJECTIVE: To investigate differences in the expression of pyroptosis-inducing cytokines in the spleen and thymus and to explore immune regulatory networks at the organ level. METHODS: Two groups of lupus mice and two groups of control mice were utilized for this study. Using the thymus and spleen of experimental animals, mRNA expression levels of five pyroptosis-inducing cytokines (interleukin 1ß, interleukin 18, NLRP3, caspase-1 and TNF-α) were determined via quantitative polymerase chain reaction. In addition, tissue distribution of these cytokines was investigated via immunohistochemistry. RESULTS: All five pyroptosis-inducing inflammatory cytokines showed higher expression in the spleen than in the thymus (p < 0.05). Moreover, the spleen/thymus expression ratios of all five pyroptosis-inducing cytokines were not statistically different between the four experimental groups. Expression of all five cytokines exhibited a stable ratio (spleen/thymus ratios). This distinctive stable spleen/thymus ratio was consistent in all four experimental groups. The stable spleen/thymus ratios of the five inflammatory cytokines were as follows: interleukin 1ß (2.02 ± 0.9), interleukin 18 (2.07 ± 1.06), caspase-1 (1.93 ± 0.66), NLRP3 (3.14 ± 1.61) and TNF-α (3.16 ± 1.36). Immunohistochemical analysis showed the cytokines were mainly expressed in the red pulp region of the spleen and the medullary region of the thymus, where immune-activated cells aggregated. CONCLUSION: The stable spleen/thymus expression ratios of pyroptosis-inducing cytokines indicated that immune organs exhibit strictly regulated functions to maintain immune homeostasis and adapt to the environment.


Assuntos
Citocinas/metabolismo , Lúpus Eritematoso Sistêmico/metabolismo , Baço/metabolismo , Timo/metabolismo , Animais , Caspase 1/metabolismo , Células Cultivadas , Feminino , Imuno-Histoquímica , Interleucina-18/metabolismo , Interleucina-1beta/metabolismo , Lúpus Eritematoso Sistêmico/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos MRL lpr , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Piroptose , RNA Mensageiro/análise , Baço/patologia , Timo/patologia , Fator de Necrose Tumoral alfa/metabolismo
7.
Immunology ; 160(1): 52-63, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32052861

RESUMO

As a pineal gland hormone, melatonin acts through its receptors to modulate the immune system. The immune system is composed of primary and secondary organs, and immune organs are adapted to the presence of the fetal alloantigen during pregnancy. However, it is unclear whether melatonin affects maternal immune organs during early pregnancy in sheep. In this study, the ovine thymus, lymph node, spleen and liver were sampled at day 16 of the oestrous cycle, and at days 13, 16 and 25 of pregnancy. The expression of melatonin receptor 1A (MT1), melatonin receptor 1B (MT2) and cluster of differentiation 4 (CD4) was detected by quantitative real-time polymerase chain reaction, Western blot and immunohistochemistry experiments. Our results showed that during early pregnancy there was an upregulation of MT1 mRNA and protein in the thymus, lymph node and liver, and there was a downregulation in the spleen. The expression of MT2 mRNA and protein was increased in the thymus but decreased in the spleen and liver, and there was no significant change in the lymph node during early pregnancy. CD4 protein was upregulated in the thymus, lymph node and liver, but there were no significant changes in the spleen during early pregnancy. In conclusion, early pregnancy induces tissue-specific expression of MT1, MT2 and CD4, which may be due to the different functions of the thymus, lymph node, spleen and liver. Further, melatonin is involved in immune regulation of the maternal thymus, lymph node, spleen and liver during early pregnancy in sheep.


Assuntos
Antígenos CD4/metabolismo , Histocompatibilidade Materno-Fetal , Melatonina/metabolismo , Prenhez/imunologia , Receptores de Melatonina/metabolismo , Ovinos/imunologia , Animais , Feminino , Perfilação da Expressão Gênica , Tolerância Imunológica , Fígado/imunologia , Fígado/metabolismo , Linfonodos/imunologia , Linfonodos/metabolismo , Gravidez , Reação em Cadeia da Polimerase em Tempo Real , Transdução de Sinais/imunologia , Baço/imunologia , Baço/metabolismo , Timo/imunologia , Timo/metabolismo , Regulação para Cima/imunologia
8.
Clin Exp Immunol ; 200(2): 176-184, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-31989577

RESUMO

The absence of adenosine deaminase (ADA) causes severe combined immune deficiency (SCID), which has been treated with PEGylated bovine-extracted ADA (ADAGEN). ADAGEN was recently replaced by a PEGylated recombinant bovine ADA, expressed in Escherichia coli (elapegademase, ELA-ADA). Limited information on ELA-ADA is available.  ADA enzymatic activity of ELA-ADA and ADAGEN was assessed in vitro at diverse dilutions. ADA activity and immune reconstitution in an ADA-SCID patient treated with ELA-ADA were compared with age-matched patients previously treated with ADAGEN. ADA activity and thymus reconstitution were evaluated in ADA-deficient mice following ELA-ADA or ADAGEN administered from 7 days postpartum. In vitro, ADA activity of ELA-ADA and ADAGEN were similar at all dilutions. In an ADA-SCID patient, ELA-ADA treatment led to a marked increase in trough plasma ADA activity, which was 20% higher than in a patient previously treated with ADAGEN. A marked increase in T cell numbers and generation of naive T cells was evident following 3 months of ELA-ADA treatment, while T cell numbers increased following 4 months in 3 patients previously treated with ADAGEN. T cell proliferations stimulation normalized and thymus shadow became evident following ELA-ADA treatment. ADA activity was significantly increased in the blood of ADA-deficient mice following ELA-ADA compared to ADAGEN, while both treatments improved the mice weights, the weight, number of cells in their thymus and thymocyte subpopulations. ELA-ADA has similar in- vitro and possibly better in-vivo activity than ADAGEN. Future studies will determine whether ELA-ADA results in improved long-term immune reconstitution.


Assuntos
Adenosina Desaminase/deficiência , Agamaglobulinemia , Imunodeficiência Combinada Severa , Linfócitos T , Timo , Adenosina Desaminase/sangue , Adenosina Desaminase/efeitos dos fármacos , Adenosina Desaminase/imunologia , Adenosina Desaminase/farmacologia , Agamaglobulinemia/sangue , Agamaglobulinemia/imunologia , Animais , Humanos , Camundongos , Camundongos Knockout , Imunodeficiência Combinada Severa/sangue , Imunodeficiência Combinada Severa/imunologia , Linfócitos T/imunologia , Linfócitos T/metabolismo , Linfócitos T/patologia , Timo/imunologia , Timo/metabolismo , Timo/patologia
9.
PLoS One ; 15(1): e0227077, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31929594

RESUMO

Gaucher disease is caused by a deficiency in glucocerebrosidase that can result in non-neuronal as well as neuronal symptoms. Common visceral symptoms are an increased organ size, specifically of the spleen, and glucosylceramide as well as glucosylsphingosine substrate accumulations as a direct result of the glucocerebrosidase deficiency. Neuronal symptoms include motor deficits and strong alterations in the cerebellum. To evaluate the effect of new compounds for the treatment of this devastating disease, animal models are needed that closely mimic the human phenotype. The 4L/PS-NA mouse as model of Gaucher disease is shown to present reduced glucocerebrosidase activity similar to human cases but an in-depth characterization of the model was still not performed. We therefore analyzed 4L/PS-NA mice for visceral alterations, motor deficits and also neuronal changes like glucocerebrosidase activity, substrate levels and neuroinflammation. A special focus was set at pathological changes of the cerebellum. Our results show that 4L/PS-NA mice have strongly enlarged visceral organs that are infiltrated by enlarged leukocytes and macrophages. Furthermore, animals present strong motor deficits that are accompanied by increased glucosylceramide and glucosylsphingosine levels in the brain, astrocytosis and activated microglia in the cortex and hippocampus as well as reduced calbindin levels in the cerebellum. The latter was directly related to a strong Purkinje cell loss. Our results thus provide a detailed characterization of the 4L/PS-NA mouse model over age showing the translational value of the model and validating its usefulness for preclinical efficiency studies to evaluate new compounds against Gaucher disease.


Assuntos
Modelos Animais de Doenças , Doença de Gaucher/genética , Glucosilceramidase/genética , Fenótipo , Animais , Cerebelo/metabolismo , Cerebelo/patologia , Feminino , Doença de Gaucher/metabolismo , Doença de Gaucher/patologia , Glucosilceramidase/metabolismo , Leucócitos/patologia , Fígado/metabolismo , Fígado/patologia , Pulmão/metabolismo , Pulmão/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Movimento , Mutação , Neurônios/metabolismo , Neurônios/patologia , Baço/metabolismo , Baço/patologia , Timo/metabolismo , Timo/patologia
10.
Cancer Sci ; 111(4): 1218-1227, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31997472

RESUMO

Enhanced degradation of tryptophan (Trp) and thus decreased plasma Trp levels are common in several types of cancers. Although it is well known that Trp catabolism is induced in the tumor microenvironment by the enzymes expressed in cancer cells, immune cells, or both, few studies have examined systemic Trp catabolism in cancer pathophysiology. The present study aimed to evaluate Trp catabolism in both tumor and peripheral tissues using tumor-engrafted Copenhagen rats that were s.c. inoculated with AT-2 rat prostate cancer cells negative for expression of Trp catabolic enzymes. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) metabolomics showed significantly decreased plasma Trp levels in AT-2 engrafted rats, accompanied by increased kynurenine/Trp ratios in spleen and thymus and serotonin levels in liver and thymus. Quantitative PCR and enzymatic activity assays showed indoleamine-2, 3-dioxygenase, an inducible enzyme that catalyzes Trp to kynurenine, was increased in tumor tissues, whereas tryptophan-2,3-dioxygenase, a major Trp catabolic enzyme that regulates systemic level of Trp, tended to be increased in the liver of AT-2 engrafted rats. Furthermore, tryptophan hydroxylase-1 (TPH1), an enzyme that catalyzes the reaction of Trp to serotonin, was significantly increased in liver and spleen of AT-2 engrafted rats. Further histochemical analysis revealed that the induction of TPH1 in the liver could be attributed to infiltration of mast cells. A similar phenomenon was observed with nonneoplastic liver samples from colorectal cancer patients. These results suggested that Trp catabolism toward serotonin synthesis might be induced in peripheral remote tissues in cancer, which could have a pathophysiological effect on cancer.


Assuntos
Neoplasias Hepáticas/genética , Fígado/metabolismo , Neoplasias da Próstata/genética , Triptofano Hidroxilase/genética , Animais , Cromatografia Líquida , Modelos Animais de Doenças , Humanos , Cinurenina/metabolismo , Fígado/patologia , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/secundário , Masculino , Mastócitos/metabolismo , Mastócitos/patologia , Metabolismo/genética , Metabolômica , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Ratos , Serotonina/genética , Serotonina/metabolismo , Baço/metabolismo , Espectrometria de Massas em Tandem , Timo/metabolismo , Microambiente Tumoral/genética
11.
Sci Rep ; 10(1): 1378, 2020 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-31992777

RESUMO

Previous work showed that the thymus can be infected by RNA viruses as HIV and HTLV-1. We thus hypothesized that the thymus might also be infected by the Zika virus (ZIKV). Herein we provide compelling evidence that ZIKV targets human thymic epithelial cells (TEC) in vivo and in vitro. ZIKV-infection enhances keratinization of TEC, with a decrease in proliferation and increase in cell death. Moreover, ZIKV modulates a high amount of coding RNAs with upregulation of genes related to cell adhesion and migration, as well as non-coding genes including miRNAs, circRNAs and lncRNAs. Moreover, we observed enhanced attachment of lymphoblastic T-cells to infected TEC, as well as virus transfer to those cells. Lastly, alterations in thymuses from babies congenitally infected were seen, with the presence of viral envelope protein in TEC. Taken together, our data reveals that the thymus, particularly the thymic epithelium, is a target for the ZIKV with changes in the expression of molecules that are relevant for interactions with developing thymocytes.


Assuntos
Células Epiteliais , Timócitos , Timo , Tropismo Viral , Infecção por Zika virus , Zika virus/fisiologia , Animais , Chlorocebus aethiops , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Células Epiteliais/virologia , Epitélio/metabolismo , Epitélio/patologia , Epitélio/virologia , Humanos , Timócitos/metabolismo , Timócitos/patologia , Timócitos/virologia , Timo/metabolismo , Timo/patologia , Timo/virologia , Células Vero , Infecção por Zika virus/metabolismo , Infecção por Zika virus/patologia
12.
Biomed Pharmacother ; 121: 109591, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31733576

RESUMO

The present study was done to evaluate the prebiotic effect of Lycium barbarum polysaccharide (LBP), its effect on murine fecal microbiota composition and innate immune response. Results showed that LBP supports the growth of selective probiotic bacteria with a maximum of 8.23 (log10 cfu/mL) and 6.62 (log10 cfu/mL) for Lactobacillus acidophilus and Bifidobacterium longum respectively. In vivo studies revealed that the administrations of LBP to mice resulted in an increase in the abundance of the phyla Proteobacteria and Firmicutes, while reducing the ratio of the phylum Bacteroidetes. At the genus level, the administration of LBP stimulated the emergence of some potential probiotic genera (Akkermansia, Lactobacillus, and Prevotellaceae). The concentrations of TGF-ß and IL-6 in serum and sIgA in the colon content were enriched significantly after LBP administrations in mice. The thymus index and spleen index of mice treated with LBP displayed significant difference compared to the control group (P < 0.05). These findings suggest that LBP is a good source as a potential prebiotic and can enhance the intestinal microbiota and boost beneficial bacteria levels, modulate innate immune response.


Assuntos
Adjuvantes Imunológicos/administração & dosagem , Medicamentos de Ervas Chinesas/administração & dosagem , Microbioma Gastrointestinal/efeitos dos fármacos , Microbioma Gastrointestinal/fisiologia , Prebióticos/administração & dosagem , Animais , Citocinas/imunologia , Citocinas/metabolismo , Camundongos , Distribuição Aleatória , Baço/efeitos dos fármacos , Baço/imunologia , Baço/metabolismo , Timo/efeitos dos fármacos , Timo/imunologia , Timo/metabolismo
13.
Nat Commun ; 10(1): 5498, 2019 12 02.
Artigo em Inglês | MEDLINE | ID: mdl-31792212

RESUMO

Interactions between thymic epithelial cells (TEC) and developing thymocytes are essential for T cell development, but molecular insights on TEC and thymus homeostasis are still lacking. Here we identify distinct transcriptional programs of TEC that account for their age-specific properties, including proliferation rates, engraftability and function. Further analyses identify Myc as a regulator of fetal thymus development to support the rapid increase of thymus size during fetal life. Enforced Myc expression in TEC induces the prolonged maintenance of a fetal-specific transcriptional program, which in turn extends the growth phase of the thymus and enhances thymic output; meanwhile, inducible expression of Myc in adult TEC similarly promotes thymic growth. Mechanistically, this Myc function is associated with enhanced ribosomal biogenesis in TEC. Our study thus identifies age-specific transcriptional programs in TEC, and establishes that Myc controls thymus size.


Assuntos
Células Epiteliais/metabolismo , Proteína Oncogênica p55(v-myc)/metabolismo , Timo/embriologia , Transcrição Genética , Animais , Células Epiteliais/citologia , Feminino , Regulação da Expressão Gênica no Desenvolvimento , Humanos , Masculino , Camundongos , Camundongos Transgênicos , Proteína Oncogênica p55(v-myc)/genética , Tamanho do Órgão , Organogênese , Timo/metabolismo
14.
Sci Rep ; 9(1): 19866, 2019 12 27.
Artigo em Inglês | MEDLINE | ID: mdl-31882694

RESUMO

The environment experienced during spaceflight may impact the immune system and the thymus appears to undergo atrophy during spaceflight. However, molecular aspects of this thymic atrophy remain to be elucidated. In this study, we analysed the thymi of mice on board the international space station (ISS) for approximately 1 month. Thymic size was significantly reduced after spaceflight. Notably, exposure of mice to 1 × g using centrifugation cages in the ISS significantly mitigated the reduction in thymic size. Although spaceflight caused thymic atrophy, the global thymic structure was not largely changed. However, RNA sequencing analysis of the thymus showed significantly reduced expression of cell cycle-regulating genes in two independent spaceflight samples. These reductions were partially countered by 1 × g exposure during the space flights. Thus, our data suggest that spaceflight leads to reduced proliferation of thymic cells, thereby reducing the size of the thymus, and exposure to 1 × g might alleviate the impairment of thymus homeostasis induced by spaceflight.


Assuntos
Gravidade Alterada , Voo Espacial , Timo/metabolismo , Animais , Sequência de Bases , Ensaio de Imunoadsorção Enzimática , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Análise de Componente Principal , RNA-Seq
15.
PLoS One ; 14(10): e0217728, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31647813

RESUMO

Regulatory T cells (Tregs) are an immunosuppressive population that are identified based on the stable expression of the fate-determining transcription factor forkhead box P3 (Foxp3). Tregs can be divided into distinct subsets based on whether they developed in the thymus (tTregs) or in the periphery (pTregs). Whether there are unique functional roles that distinguish pTregs and tTregs remains largely unclear. To elucidate these functions, efforts have been made to specifically identify and modify individual Treg subsets. Deletion of the conserved non-coding sequence (CNS)1 in the Foxp3 locus leads to selective impairment of pTreg generation without disrupting tTreg generation in the C57BL/6J background. Using CRISPR-Cas9 genome editing technology, we removed the Foxp3 CNS1 region in the non-obese diabetic (NOD) mouse model of spontaneous type 1 diabetes mellitus (T1D) to determine if pTregs contribute to autoimmune regulation. Deletion of CNS1 impaired in vitro induction of Foxp3 in naïve NOD CD4+ T cells, but it did not alter Tregs in most lymphoid and non-lymphoid tissues analyzed except for the large intestine lamina propria, where a small but significant decrease in RORγt+ Tregs and corresponding increase in Helios+ Tregs was observed in NOD CNS1-/- mice. CNS1 deletion also did not alter the development of T1D or glucose tolerance despite increased pancreatic insulitis in pre-diabetic female NOD CNS1-/- mice. Furthermore, the proportions of autoreactive Tregs and conventional T cells (Tconvs) within pancreatic islets were unchanged. These results suggest that pTregs dependent on the Foxp3 CNS1 region are not the dominant regulatory population controlling T1D in the NOD mouse model.


Assuntos
Diabetes Mellitus Tipo 1/imunologia , Modelos Animais de Doenças , Fatores de Transcrição Forkhead/imunologia , Linfócitos T Reguladores/imunologia , Timo/imunologia , Animais , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/imunologia , Proteínas de Ligação a DNA/metabolismo , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/metabolismo , Feminino , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , Camundongos Knockout , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/genética , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/imunologia , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/metabolismo , Linfócitos T Reguladores/metabolismo , Timo/citologia , Timo/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/imunologia , Fatores de Transcrição/metabolismo
16.
J Therm Biol ; 85: 102420, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31657761

RESUMO

The purpose of the current study was to investigate that effect of duration of thermal stress on growth performance, oxidative stress indices in serum, the expression and localization of ABCG2, and mitochondria ROS production in skeletal muscle, small intestine and immune organs, and then to further reveal correlations between indicators. At 28 days of age, sixty broilers were randomly divided into the control group (25 ±â€¯2 °C; 24 h/day) and the heat stress group (36 ±â€¯2 °C; 8 h/day lasted for 1 week or 2 weeks). Fifteen broilers per group were respectively euthanized, and some samples were respectively collected from the control and the heat stress groups at the end of the 1st week or the 2nd week of heat stress. A typical heat stress response has been observed at this temperature. Compared with the control group, the birds subjected to heat stress at the end of the 1st week reduced (P < 0.05) body weight (BW), average daily feed intake (ADFI), average daily gain (ADG), the activity of serum antioxidant enzyme and content of glutathione (GSH), while increased (P < 0.05) feed conversion ratio (FCR), serum corticosterone and malondialdehyde (MDA) levels. However, when the heat stress lasted for the end of the 2nd week, there was no significant difference (P > 0.05) in ADFI, ADG, FCR and serum contents of corticosterone, MDA and GSH. Regardless of duration of thermal stress, the localization of ABCG2 protein had no change. Moreover, heat stress also did not affect (P > 0.05) the IOD of the ABCG2 positive portion and the expression of the ABCG2 mRNA in the pectorales, crureus, duodenum, jejunum, ileum and spleen, while significantly increased (P < 0.05) the corresponding tissues ROS production at the end of the 1st week of heat stress. In contrast, at the end of the 2nd week of heat stress, IOD of the ABCG2 positive portion and the expression of the ABCG2 mRNA in heat stress group significantly increased (P < 0.05), while the corresponding tissues ROS production had no difference (P > 0.05) compared to the control group. Collectively, duration of thermal stress affects growth performance, serum oxidative stress indices, and the expression of ABCG2 and the ROS production of broiler tissues in a time-dependent manner. There is a negative correlation between the expression of ABCG2 and the ROS production in the corresponding tissues under heat stress.


Assuntos
Galinhas/fisiologia , Transtornos de Estresse por Calor/metabolismo , Transtornos de Estresse por Calor/veterinária , Doenças das Aves Domésticas/metabolismo , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Animais , Catalase/sangue , Galinhas/sangue , Corticosterona/sangue , Glutationa/sangue , Glutationa Peroxidase/sangue , Glutationa Redutase/sangue , Intestino Delgado/metabolismo , Malondialdeído/sangue , Mitocôndrias/metabolismo , Músculo Esquelético/metabolismo , Estresse Oxidativo , Espécies Reativas de Oxigênio/metabolismo , Baço/metabolismo , Superóxido Dismutase/sangue , Timo/metabolismo
17.
Immunity ; 51(5): 930-948.e6, 2019 11 19.
Artigo em Inglês | MEDLINE | ID: mdl-31604687

RESUMO

Generation of the first T lymphocytes in the human embryo involves the emergence, migration, and thymus seeding of lymphoid progenitors together with concomitant thymus organogenesis, which is the initial step to establish the entire adaptive immune system. However, the cellular and molecular programs regulating this process remain unclear. We constructed a single-cell transcriptional landscape of human early T lymphopoiesis by using cells from multiple hemogenic and hematopoietic sites spanning embryonic and fetal stages. Among heterogenous early thymic progenitors, one subtype shared common features with a subset of lymphoid progenitors in fetal liver that are known as thymus-seeding progenitors. Unbiased bioinformatics analysis identified a distinct type of pre-thymic lymphoid progenitors in the aorta-gonad-mesonephros (AGM) region. In parallel, we investigated thymic epithelial cell development and potential cell-cell interactions during thymus organogenesis. Together, our data provide insights into human early T lymphopoiesis that prospectively direct T lymphocyte regeneration, which might lead to development of clinical applications.


Assuntos
Diferenciação Celular/genética , Linfopoese/genética , Organogênese/genética , Células Precursoras de Linfócitos T/citologia , Células Precursoras de Linfócitos T/metabolismo , Timo/embriologia , Biomarcadores , Diferenciação Celular/imunologia , Embrião de Mamíferos , Desenvolvimento Embrionário/genética , Perfilação da Expressão Gênica , Células-Tronco Hematopoéticas/citologia , Células-Tronco Hematopoéticas/metabolismo , Humanos , Imunofenotipagem , Linfopoese/imunologia , Detecção de Sinal Psicológico , Linfócitos T/imunologia , Linfócitos T/metabolismo , Timo/imunologia , Timo/metabolismo , Transcriptoma
18.
Genes Dev ; 33(17-18): 1117-1135, 2019 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-31481536

RESUMO

T-cell development in mammals is a model for lineage choice and differentiation from multipotent stem cells. Although T-cell fate choice is promoted by signaling in the thymus through one dominant pathway, the Notch pathway, it entails a complex set of gene regulatory network and chromatin state changes even before the cells begin to express their signature feature, the clonal-specific T-cell receptors (TCRs) for antigen. This review distinguishes three developmental modules for T-cell development, which correspond to cell type specification, TCR expression and selection, and the assignment of cells to different effector types. The first is based on transcriptional regulatory network events, the second is dominated by somatic gene rearrangement and mutation and cell selection, and the third corresponds to establishing a poised state of latent regulator priming through an unknown mechanism. Interestingly, in different lineages, the third module can be deployed at variable times relative to the completion of the first two modules. This review focuses on the gene regulatory network and chromatin-based kinetic constraints that determine activities of transcription factors TCF1, GATA3, PU.1, Bcl11b, Runx1, and E proteins in the primary establishment of T-cell identity.


Assuntos
Diferenciação Celular , Regulação da Expressão Gênica no Desenvolvimento , Linfócitos T/citologia , Animais , Diferenciação Celular/genética , Linhagem da Célula , Cromatina/metabolismo , Redes Reguladoras de Genes , Hematopoese , Linfócitos T/metabolismo , Timo/citologia , Timo/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
19.
Proc Natl Acad Sci U S A ; 116(38): 19090-19097, 2019 09 17.
Artigo em Inglês | MEDLINE | ID: mdl-31481626

RESUMO

Aberrant T cell development is a pivotal risk factor for autoimmune disease; however, the underlying molecular mechanism of T cell overactivation is poorly understood. Here, we identified NF-κB-inducing kinase (NIK) and IkB kinase α (IKKα) in thymic epithelial cells (TECs) as essential regulators of T cell development. Mouse TEC-specific ablation of either NIK or IKKα resulted in severe T cell-mediated inflammation, injury, and fibrosis in the liver and lung, leading to premature death within 18 d of age. NIK or IKKα deficiency abrogated medullary TEC development, and led to breakdown of central tolerance, production of autoreactive T cells, and fatal autoimmune destruction in the liver and lung. TEC-specific ablation of NIK or IKKα also impaired thymic T cell development from the double-negative through the double-positive stages and inhibited peripheral B cell development. These results unravel a hitherto unrecognized essential role of TEC-intrinsic NIK and IKKα pathways in autoimmunity and T cell-instigated chronic liver and lung diseases.


Assuntos
Autoimunidade/imunologia , Quinase I-kappa B/fisiologia , Inflamação/imunologia , Fígado/imunologia , Pulmão/imunologia , Proteínas Serina-Treonina Quinases/fisiologia , Timo/imunologia , Animais , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD4-Positivos/patologia , Diferenciação Celular , Células Epiteliais/imunologia , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Feminino , Homeostase , Inflamação/metabolismo , Inflamação/patologia , Fígado/metabolismo , Fígado/patologia , Pulmão/metabolismo , Pulmão/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , NF-kappa B/metabolismo , Timo/metabolismo , Timo/patologia
20.
Histochem Cell Biol ; 152(6): 397-413, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31552487

RESUMO

The mechanisms that determine the commitment of thymic epithelial precursors to the two major thymic epithelial cell lineages, cTECs and mTECs, remain unknown. Here we show that FoxN1 nu mutation, which abolishes thymic epithelium differentiation, results in the formation of a tubular branched structure according to a typical branching morphogenesis and tubulogenesis developmental pattern. In the presence of FoxN1, in alymphoid NSG and fetal Ikaros-/- thymi, there is no lumen formation and only partial apical differentiation. This initiates cortex-medulla differentiation inducing expression of medullary genes in the apically differentiating cells and of cortical genes in the non-apically differentiating cells, which will definitely differentiate in wt and postnatal Ikaros-/- mice. Therefore, the thymus development is based on a branching morphogenesis and tubulogenesis developmental pattern: FoxN1 expression in the thymic primordium inhibits tubulogenesis and induces the expression of genes involved in TEC differentiation, which culminates with the expression of functional cell markers, i.e., MHCII, CD80, Aire in both postnatal Ikaros-/- and WT thymi after arrival of lymphoid progenitor cells.


Assuntos
Células Epiteliais/metabolismo , Fatores de Transcrição Forkhead/metabolismo , Timo/metabolismo , Animais , Diferenciação Celular , Fatores de Transcrição Forkhead/análise , Camundongos , Camundongos Endogâmicos NOD , Camundongos Nus , Camundongos SCID , Morfogênese , Timo/química , Timo/citologia
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