Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 1.272
Filtrar
1.
PLoS Biol ; 17(10): e3000383, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31661488

RESUMO

Thymic involution and proliferation of naive T cells both contribute to shaping the naive T-cell repertoire as humans age, but a clear understanding of the roles of each throughout a human life span has been difficult to determine. By measuring nuclear bomb test-derived 14C in genomic DNA, we determined the turnover rates of CD4+ and CD8+ naive T-cell populations and defined their dynamics in healthy individuals ranging from 20 to 65 years of age. We demonstrate that naive T-cell generation decreases with age because of a combination of declining peripheral division and thymic production during adulthood. Concomitant decline in T-cell loss compensates for decreased generation rates. We investigated putative mechanisms underlying age-related changes in homeostatic regulation of CD4+ naive T-cell turnover, using mass cytometry to profile candidate signaling pathways involved in T-cell activation and proliferation relative to CD31 expression, a marker of thymic proximity for the CD4+ naive T-cell population. We show that basal nuclear factor κB (NF-κB) phosphorylation positively correlated with CD31 expression and thus is decreased in peripherally expanded naive T-cell clones. Functionally, we found that NF-κB signaling was essential for naive T-cell proliferation to the homeostatic growth factor interleukin (IL)-7, and reduced NF-κB phosphorylation in CD4+CD31- naive T cells is linked to reduced homeostatic proliferation potential. Our results reveal an age-related decline in naive T-cell turnover as a putative regulator of naive T-cell diversity and identify a molecular pathway that restricts proliferation of peripherally expanded naive T-cell clones that accumulate with age.


Assuntos
Envelhecimento/imunologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Linhagem da Célula/imunologia , Homeostase/imunologia , Timo/imunologia , Adulto , Idoso , Envelhecimento/genética , Linfócitos T CD4-Positivos/citologia , Linfócitos T CD8-Positivos/citologia , Linhagem da Célula/genética , Proliferação de Células , Feminino , Regulação da Expressão Gênica no Desenvolvimento , Homeostase/genética , Humanos , Imunofenotipagem , Interleucina-7/genética , Interleucina-7/imunologia , Ativação Linfocitária , Masculino , Pessoa de Meia-Idade , NF-kappa B/genética , NF-kappa B/imunologia , Fosforilação , Molécula-1 de Adesão Celular Endotelial a Plaquetas/genética , Molécula-1 de Adesão Celular Endotelial a Plaquetas/imunologia , Transdução de Sinais , Timo/citologia , Timo/crescimento & desenvolvimento
2.
Arq. bras. med. vet. zootec. (Online) ; 71(4): 1269-1276, jul.-ago. 2019. ilus
Artigo em Português | LILACS, VETINDEX | ID: biblio-1038603

RESUMO

Objetivou-se descrever comparativamente as artérias responsáveis pela irrigação dos lobos tímicos cervicais e torácicos dos javalis, determinando-se também as características morfológicas do referido órgão nessa espécie, a ponto de correlacioná-las evolutivamente com os demais representantes da família Suidae. Os lobos tímicos cervicais direito e esquerdo receberam ramos distribuídos pelas artérias carótidas comuns direita e esquerda e cervicais superficiais direita e esquerda e, por vezes, pelas artérias torácica externa esquerda e subclávia esquerda. Essa característica vascular foi mantida ao longo da evolução, estando presente em linhagens e raças mais recentes de suídeos. A irrigação dos lobos tímicos torácicos direito e esquerdo foi realizada predominantemente por ramos diretos e indiretos ipsilaterais e contralaterais das artérias torácicas internas direita e esquerda, e também por ramos da artéria subclávia esquerda. Ramos diretos das artérias cervicais superficiais direita e esquerda e ramos diretos da artéria torácica interna direita foram encontrados para o lobo tímico médio, sendo essa uma descrição única nessa espécie, o que demonstra uma característica evolutiva primitiva nesse ancestral.(AU)


The objective of this study was to comparatively describe the arteries responsible for the irrigation of the cervical and thoracic thymus lobes of Boars, also determining the morphological characteristics of this body in this species to the point of evolutionarily correlating them with other representatives of the Suidae family. The left and right cervical thymic lobes received branches distributed by common right and left, superficial right and left carotid arteries, and neck and, sometimes, the outer left chest and left subclavian arteries. This feature was vascular maintained throughout evolution and is present in more recent strains and breeds of swine. Irrigation of the right and left thoracic thymic lobes was performed predominantly by direct and indirect ipsilateral and contralateral branches of the right and left internal thoracic arteries and also by branches of the left subclavian artery. Direct branches of the right and left superficial cervical artery and right branches of the right internal thoracic artery were found for the average thymic lobe, this being a unique description in this species, demonstrating a primitive feature in this evolutionary ancestor.(AU)


Assuntos
Animais , Timo/crescimento & desenvolvimento , Timo/irrigação sanguínea , Artérias Carótidas , Sus scrofa/anatomia & histologia
3.
Nat Commun ; 10(1): 3031, 2019 07 10.
Artigo em Inglês | MEDLINE | ID: mdl-31292453

RESUMO

Maternal immune dysregulation seems to affect fetal or postnatal immune development. Preeclampsia is a pregnancy-associated disorder with an immune basis and is linked to atopic disorders in offspring. Here we show reduction of fetal thymic size, altered thymic architecture and reduced fetal thymic regulatory T (Treg) cell output in preeclamptic pregnancies, which persists up to 4 years of age in human offspring. In germ-free mice, fetal thymic CD4+ T cell and Treg cell development are compromised, but rescued by maternal supplementation with the intestinal bacterial metabolite short chain fatty acid (SCFA) acetate, which induces upregulation of the autoimmune regulator (AIRE), known to contribute to Treg cell generation. In our human cohorts, low maternal serum acetate is associated with subsequent preeclampsia, and correlates with serum acetate in the fetus. These findings suggest a potential role of acetate in the pathogenesis of preeclampsia and immune development in offspring.


Assuntos
Acetatos/sangue , Feto/imunologia , Pré-Eclâmpsia/imunologia , Efeitos Tardios da Exposição Pré-Natal/imunologia , Linfócitos T Reguladores/imunologia , Acetatos/administração & dosagem , Acetatos/imunologia , Acetatos/metabolismo , Adulto , Animais , Animais Recém-Nascidos , Estudos de Casos e Controles , Desenvolvimento Infantil , Pré-Escolar , Suplementos Nutricionais , Feminino , Feto/citologia , Feto/diagnóstico por imagem , Microbioma Gastrointestinal/imunologia , Vida Livre de Germes/imunologia , Humanos , Tolerância Imunológica/imunologia , Lactente , Recém-Nascido , Estudos Longitudinais , Troca Materno-Fetal/imunologia , Camundongos , Tamanho do Órgão/imunologia , Pré-Eclâmpsia/sangue , Pré-Eclâmpsia/diagnóstico , Gravidez , Efeitos Tardios da Exposição Pré-Natal/patologia , Efeitos Tardios da Exposição Pré-Natal/prevenção & controle , Estudos Prospectivos , Timo/citologia , Timo/diagnóstico por imagem , Timo/crescimento & desenvolvimento , Timo/imunologia , Fatores de Transcrição/imunologia , Fatores de Transcrição/metabolismo , Ultrassonografia Pré-Natal , Adulto Jovem
4.
Dev Comp Immunol ; 99: 103396, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31125574

RESUMO

Porcine thymus contains three independent populations of cells that have rearranged immunoglobulin heavy chain VDJH genes. The first population can be found exclusively in medulla and it consists of existing mature B cells and plasma cells. The second consists of developing B cells characterized by the presence of selected VDJH rearrangement, similar to B cell lymphogenesis in the bone marrow. The third population is entirely unaffected by selection mechanism for productive VDJH rearrangement and represents T lineage cells that rearrange immunoglobulin genes. Transcription of unselected VDJH repertoire is not allowed in T cells. Sequence analysis of unselected VDJH repertoire from T cells also revealed important consequences for B cell lymphogenesis and selection of B cell repertoire. As far as we know, this is the first evidence that some species completely rearrange VDJH genes in T cells. Our results also support the finding that B cells actively develop in the thymus.


Assuntos
Genes de Cadeia Pesada de Imunoglobulina/genética , Subpopulações de Linfócitos/imunologia , Suínos/imunologia , Linfócitos T/imunologia , Animais , Linfócitos B/imunologia , Feto/imunologia , Humanos , Especificidade da Espécie , Suínos/genética , Suínos/crescimento & desenvolvimento , Timo/crescimento & desenvolvimento , Timo/imunologia , Recombinação V(D)J/genética
5.
Anim Sci J ; 90(6): 747-756, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30989748

RESUMO

This study was designed to evaluate the potential application of the stems and leaves of Astragalus membranaceus (AMSL) in the poultry industry. Quails were divided into four groups and fed daily with an AMSL-free diet (control) or with 1%, 3%, or 5% (w/w) AMSL-incorporated diets for 35 days. The results showed that supplementing AMSL in the diet, especially at a concentration of 3%, increased daily gain and feed intake during the entire experiment (p < 0.05). The immune organ development of the thymus and bursa of Fabricius was promoted, and the immune system was enhanced by increasing the quantities of IgA and complements C3 and C4 (p < 0.05). The total antioxidant capacity and the activities of glutathione peroxidase and catalase were increased (p < 0.05). Moreover, the 3%-5% AMSL groups regulated the intestinal flora by promoting the proliferation of lactic acid bacteria and inhibiting the growth of coliform bacteria (p < 0.05). In conclusion, feeding incorporated diets with appropriate AMSL levels significantly increased growth performance, strengthened the immune system, improved antioxidative status, and regulated the intestinal microflora of quails, suggesting that AMSL has the potential to serve as a feed additive in the poultry industry.


Assuntos
Astragalus propinquus , Dieta/veterinária , Suplementos Nutricionais , Microbioma Gastrointestinal , Caules de Planta , Codorniz/crescimento & desenvolvimento , Codorniz/imunologia , Ração Animal , Animais , Antioxidantes/metabolismo , Bolsa de Fabricius/crescimento & desenvolvimento , Bolsa de Fabricius/imunologia , Complemento C3 , Complemento C4 , Imunoglobulina A , Folhas de Planta , Codorniz/metabolismo , Codorniz/microbiologia , Timo/crescimento & desenvolvimento , Timo/imunologia
6.
Nat Commun ; 10(1): 1037, 2019 03 04.
Artigo em Inglês | MEDLINE | ID: mdl-30833563

RESUMO

IL-2R signaling is essential for regulatory T cell (Treg) function. However, the precise contribution of IL-2 during Treg thymic development, peripheral homeostasis and lineage stability remains unclear. Here we show that IL-2R signaling is required by thymic Tregs at an early step for expansion and survival, and a later step for functional maturation. Using inducible, conditional deletion of CD25 in peripheral Tregs, we also find that IL-2R signaling is indispensable for Treg homeostasis, whereas Treg lineage stability is largely IL-2-independent. CD25 knockout peripheral Tregs have increased apoptosis, oxidative stress, signs of mitochondrial dysfunction, and reduced transcription of key enzymes of lipid and cholesterol biosynthetic pathways. A divergent IL-2R transcriptional signature is noted for thymic Tregs versus peripheral Tregs. These data indicate that IL-2R signaling in the thymus and the periphery leads to distinctive effects on Treg function, while peripheral Treg survival depends on a non-conventional mechanism of metabolic regulation.


Assuntos
Homeostase , Subunidade beta de Receptor de Interleucina-2/metabolismo , Organogênese , Transdução de Sinais , Linfócitos T Reguladores/metabolismo , Timo/crescimento & desenvolvimento , Animais , Apoptose , Vias Biossintéticas , Citocinas/metabolismo , Feminino , Subunidade alfa de Receptor de Interleucina-2/genética , Subunidade alfa de Receptor de Interleucina-2/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Mitocôndrias/metabolismo , Estresse Oxidativo , Fenótipo , Pele/patologia , Timo/imunologia
7.
Biochem Biophys Res Commun ; 511(4): 935-940, 2019 04 16.
Artigo em Inglês | MEDLINE | ID: mdl-30853180

RESUMO

BACKGROUND/AIMS: The expression of transcription factor Zbtb1 is essential for the maintenance and development of various blood cells in the hematopoietic system. In the current study, we found that the total number of thymocytes in PLZF deficient mice was reduced compared with thymocytes in wild-type mice, and the number of early T-cell progenitors decreased. However, the decrease of thymocytes in PLZF deficient mice was not cell intrinsic. This study adds new information regarding the regulation of the PLZF gene in the development and self-renewal of T cells. METHODS: The thymus was isolated from newborn mice, and the two lobes of each thymus were physically separated. Each host received a thymus, two lobes, each placed at one end of the kidney, as described in the literature. Tail vein blood was periodically collected from some of the recipients and analyzed for the presence of peripheral blood T cells. RESULTS: In PLZF-EGFP reporter mice and neonatal thymus transplantation to the kidney, we found that PLZF was highly expressed in DN1 (Lineage-CD44+CD25-) cells of thymic grafts of Rag2/γc-/- recipient mice. We found that the proportion of PLZF wild-type and mutant-derived cells in the thymocytes of recipient mice after bone marrow transplantation is approximately equal to the competitive bone marrow chimeric mouse model, and all mice contain a normal thymus. CONCLUSION: The development of T cells suggests that the effect of the PLZF gene on T cell differentiation and development is not cell intrinsic. However, in the neonatal mouse thymic transplant model in the Rag2/γc-/- recipient mouse, deletion of the PLZF gene results in a significant decrease in the proportion of DN1 cells from the donor in the thymic graft.


Assuntos
Regulação da Expressão Gênica no Desenvolvimento , Proteína com Dedos de Zinco da Leucemia Promielocítica/genética , Linfócitos T/citologia , Animais , Contagem de Células , Autorrenovação Celular , Deleção de Genes , Camundongos , Camundongos Endogâmicos C57BL , Linfócitos T/metabolismo , Timócitos/citologia , Timócitos/metabolismo , Timo/citologia , Timo/crescimento & desenvolvimento , Timo/metabolismo
8.
Nat Immunol ; 20(2): 195-205, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30643267

RESUMO

The developmental programs that generate a broad repertoire of regulatory T cells (Treg cells) able to respond to both self antigens and non-self antigens remain unclear. Here we found that mature Treg cells were generated through two distinct developmental programs involving CD25+ Treg cell progenitors (CD25+ TregP cells) and Foxp3lo Treg cell progenitors (Foxp3lo TregP cells). CD25+ TregP cells showed higher rates of apoptosis and interacted with thymic self antigens with higher affinity than did Foxp3lo TregP cells, and had a T cell antigen receptor repertoire and transcriptome distinct from that of Foxp3lo TregP cells. The development of both CD25+ TregP cells and Foxp3lo TregP cells was controlled by distinct signaling pathways and enhancers. Transcriptomics and histocytometric data suggested that CD25+ TregP cells and Foxp3lo TregP cells arose by coopting negative-selection programs and positive-selection programs, respectively. Treg cells derived from CD25+ TregP cells, but not those derived from Foxp3lo TregP cells, prevented experimental autoimmune encephalitis. Our findings indicate that Treg cells arise through two distinct developmental programs that are both required for a comprehensive Treg cell repertoire capable of establishing immunotolerance.


Assuntos
Diferenciação Celular/imunologia , Encefalomielite Autoimune Experimental/imunologia , Células Progenitoras Linfoides/fisiologia , Linfócitos T Reguladores/fisiologia , Timo/crescimento & desenvolvimento , Animais , Autoantígenos/imunologia , Colite/imunologia , Modelos Animais de Doenças , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/metabolismo , Adjuvante de Freund/administração & dosagem , Adjuvante de Freund/imunologia , Humanos , Tolerância Imunológica/imunologia , Subunidade alfa de Receptor de Interleucina-2/metabolismo , Células Progenitoras Linfoides/transplante , Camundongos , Camundongos Transgênicos , Mycobacterium tuberculosis/imunologia , Glicoproteína Mielina-Oligodendrócito/administração & dosagem , Glicoproteína Mielina-Oligodendrócito/imunologia , Fragmentos de Peptídeos/administração & dosagem , Fragmentos de Peptídeos/imunologia , Transdução de Sinais , Organismos Livres de Patógenos Específicos , Timo/citologia , Timo/imunologia
9.
Anat Sci Int ; 94(1): 111-118, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30155680

RESUMO

The increase in autoimmune diseases in recent years has drawn attention back to the thymus, with new approaches to improve and/or restore immune function being investigated. As the primary lymphoid organ responsible for functional T cell development, studies on the pre-/post-natal development of this organ and T lymphocytes in human and other species are of special interest. During our screening studies we observed structures that had not been described or mentioned previously, and named them "epitheliostromal sheaths". Associated with these unique structures were also small attached lobules (possibly reflecting the maturational stages of thymic lobules), which the authors consider as markers of histogenesis and the growth of the organ during early childhood; these findings are thus presented to researchers in this field. Approximately 1000 sections prepared from infantile thymic tissues of partial biopsy specimens were immunostained and examined. Specimens were taken from ten patients (with informed consent) in the age range of 4-9 years who underwent surgery due to congenital cardiovascular anomalies but were otherwise normal. Digital images of interest were captured to describe them in detail. Determining the immunophenotype of the compartments in these newly developing lobules assisted us greatly in defining compartments and their growth order. In summary, our findings suggest a niche-based thymus growth mechanism during childhood. We presented our findings, hoping to provide additional insight to researchers aiming to restore thymus function in adulthood and improve its immunological functions.


Assuntos
Desenvolvimento Infantil , Timo/crescimento & desenvolvimento , Animais , Biópsia , Diferenciação Celular/fisiologia , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Linfócitos T/fisiologia
10.
Sci Transl Med ; 10(457)2018 09 05.
Artigo em Inglês | MEDLINE | ID: mdl-30185651

RESUMO

The thymus is the primary lymphoid organ where naïve T cells are generated; however, with the exception of age, the parameters that govern its function in healthy humans remain unknown. We characterized the variability of thymic function among 1000 age- and sex-stratified healthy adults of the Milieu Intérieur cohort, using quantification of T cell receptor excision circles (TRECs) in peripheral blood T cells as a surrogate marker of thymopoiesis. Age and sex were the only nonheritable factors identified that affect thymic function. TREC amounts decreased with age and were higher in women compared to men. In addition, a genome-wide association study revealed a common variant (rs2204985) within the T cell receptor TCRA-TCRD locus, between the DD2 and DD3 gene segments, which associated with TREC amounts. Strikingly, transplantation of human hematopoietic stem cells with the rs2204985 GG genotype into immunodeficient mice led to thymopoiesis with higher TRECs, increased thymocyte counts, and a higher TCR repertoire diversity. Our population immunology approach revealed a genetic locus that influences thymopoiesis in healthy adults, with potentially broad implications in precision medicine.


Assuntos
Loci Gênicos , Variação Genética , Receptores de Antígenos de Linfócitos T alfa-beta/genética , Receptores de Antígenos de Linfócitos T gama-delta/genética , Timo/crescimento & desenvolvimento , Adulto , Idoso , Animais , Biomarcadores/metabolismo , Estudos de Coortes , Feminino , Estudo de Associação Genômica Ampla , Humanos , Masculino , Camundongos SCID , Pessoa de Meia-Idade , Fenótipo , Linfócitos T/metabolismo , Adulto Jovem
11.
Sci Rep ; 8(1): 13169, 2018 09 03.
Artigo em Inglês | MEDLINE | ID: mdl-30177771

RESUMO

AIRE expression in thymus is downregulated by estrogen after puberty, what probably renders women more susceptible to autoimmune disorders. Here we investigated the effects of minipuberty on male and female infant human thymic tissue in order to verify if this initial transient increase in sex hormones - along the first six months of life - could affect thymic transcriptional network regulation and AIRE expression. Gene co-expression network analysis for differentially expressed genes and miRNA-target analysis revealed sex differences in thymic tissue during minipuberty, but such differences were not detected in the thymic tissue of infants aged 7-18 months, i.e. the non-puberty group. AIRE expression was essentially the same in both sexes in minipuberty and in non-puberty groups, as assessed by genomic and immunohistochemical assays. However, AIRE-interactors networks showed several differences in all groups regarding gene-gene expression correlation. Therefore, minipuberty and genomic mechanisms interact in shaping thymic sexual dimorphism along the first six months of life.


Assuntos
Regulação da Expressão Gênica no Desenvolvimento , Redes Reguladoras de Genes , MicroRNAs/genética , Caracteres Sexuais , Timo/metabolismo , Fatores de Transcrição/genética , Estrogênios/metabolismo , Feminino , Perfilação da Expressão Gênica , Ontologia Genética , Humanos , Lactente , Masculino , MicroRNAs/classificação , MicroRNAs/metabolismo , Anotação de Sequência Molecular , Fatores Sexuais , Timo/crescimento & desenvolvimento , Fatores de Transcrição/metabolismo
12.
Development ; 145(16)2018 08 13.
Artigo em Inglês | MEDLINE | ID: mdl-30042180

RESUMO

T-cell development is a complex dynamic process that relies on ordered stromal signals delivered to thymus-seeding progenitors that migrate throughout different thymus microenvironments (TMEs). Particularly, Notch signaling provided by thymic epithelial cells (TECs) is crucial for T-cell fate specification and generation of mature T cells. Four canonical Notch ligands (Dll1, Dll4, Jag1 and Jag2) are expressed in the thymus, but their spatial distribution in functional TMEs is largely unknown, especially in humans, and their impact on Notch1 activation during T-lymphopoiesis remains undefined. Based on immunohistochemistry and quantitative confocal microscopy of fetal, postnatal and adult human and mouse thymus samples, we show that spatial regulation of Notch ligand expression defines discrete Notch signaling niches and dynamic species-specific TMEs. We further show that Notch ligand expression, particularly DLL4, is tightly regulated in cortical TECs during human thymus ontogeny and involution. Also, we provide the first evidence that NOTCH1 activation is induced in vivo in CD34+ progenitors and developing thymocytes at particular cortical niches of the human fetal and postnatal thymus. Collectively, our results show that human thymopoiesis involves complex spatiotemporal regulation of Notch ligand expression, which ensures the coordinated delivery of niche-specific NOTCH1 signals required for dynamic T-cell development.


Assuntos
Receptor Notch1/metabolismo , Timo/crescimento & desenvolvimento , Timo/metabolismo , Adolescente , Adulto , Envelhecimento/metabolismo , Animais , Antígenos CD34/metabolismo , Criança , Feto/embriologia , Regulação da Expressão Gênica no Desenvolvimento , Humanos , Lactente , Recém-Nascido , Ligantes , Camundongos , Camundongos Endogâmicos C57BL , Organogênese , Proteínas Serrate-Jagged/metabolismo , Transdução de Sinais , Células-Tronco/metabolismo , Células Estromais/citologia , Células Estromais/metabolismo , Timócitos/citologia , Timócitos/metabolismo , Timo/citologia , Timo/embriologia
13.
Nutrients ; 10(7)2018 Jul 18.
Artigo em Inglês | MEDLINE | ID: mdl-30021962

RESUMO

Aging is the main factor involved in the onset of degenerative diseases. Dietary protein restriction has been shown to increase the lifespan of rodents and improve metabolic phenotype. Branched-chain amino acids (BCAA) can act as nutrient signals that increase the lifespan of mice after prolonged supplementation. It remains unclear whether the combination of protein restriction and BCAA supplementation improves metabolic and immunological profiles during aging. Here, we investigated how dietary protein levels and BCAA supplementation impact metabolism and immune profile during a 12-month intervention in adult male C57BL/6J mice. We found that protein restriction improved insulin tolerance and increased hepatic fibroblast growth factor 21 mRNA, circulating interleukin (IL)-5 concentration, and thermogenic uncoupling protein 1 in subcutaneous white fat. Surprisingly, BCAA supplementation conditionally increased body weight, lean mass, and fat mass, and deteriorated insulin intolerance during protein restriction, but not during protein sufficiency. BCAA also induced pro-inflammatory gene expression in visceral adipose tissue under both normal and low protein conditions. These results suggest that dietary protein levels and BCAA supplementation coordinate a complex regulation of metabolism and tissue inflammation during prolonged feeding.


Assuntos
Envelhecimento , Aminoácidos de Cadeia Ramificada/uso terapêutico , Dieta com Restrição de Proteínas , Proteínas na Dieta/uso terapêutico , Suplementos Nutricionais , Regulação da Expressão Gênica no Desenvolvimento , Sarcopenia/prevenção & controle , Adiposidade , Aminoácidos de Cadeia Ramificada/efeitos adversos , Aminoácidos de Cadeia Ramificada/metabolismo , Animais , Citocinas/sangue , Dieta com Restrição de Proteínas/efeitos adversos , Proteínas na Dieta/efeitos adversos , Proteínas na Dieta/metabolismo , Suplementos Nutricionais/efeitos adversos , Perfilação da Expressão Gênica , Resistência à Insulina , Fígado/crescimento & desenvolvimento , Fígado/imunologia , Fígado/metabolismo , Fígado/patologia , Masculino , Camundongos Endogâmicos C57BL , Tamanho do Órgão , Proteômica/métodos , Distribuição Aleatória , Sarcopenia/imunologia , Sarcopenia/metabolismo , Sarcopenia/patologia , Baço/crescimento & desenvolvimento , Baço/imunologia , Baço/metabolismo , Baço/patologia , Gordura Subcutânea Abdominal/crescimento & desenvolvimento , Gordura Subcutânea Abdominal/imunologia , Gordura Subcutânea Abdominal/metabolismo , Gordura Subcutânea Abdominal/patologia , Timo/crescimento & desenvolvimento , Timo/imunologia , Timo/metabolismo , Timo/patologia , Ganho de Peso
14.
Eur J Immunol ; 48(9): 1481-1491, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29851080

RESUMO

Members of the innate lymphoid cell (ILC) family have been implicated in the development of thymic microenvironments and the recovery of this architecture after damage. However, a detailed characterization of this family in the thymus is lacking. To better understand the thymic ILC compartment, we have utilized multiple in vivo models including the fate mapping of inhibitor of DNA binding-2 (Id2) expression and the use of Id2 reporter mice. Our data demonstrate that ILCs are more prominent immediately after birth, but were rapidly diluted as the T-cell development program increased. As observed in the embryonic thymus, CCR6+ NKp46- lymphoid tissue inducer (LTi) cells were the main ILC3 population present, but numbers of these cells swiftly declined in the neonate and ILC3 were barely detectable in adult thymus. This loss of ILC3 means ILC2 are the dominant ILC population in the thymus. Thymic ILC2 were able to produce IL-5 and IL-13, were located within the medulla, and did not result from ILC3 plasticity. Furthermore, in WT mice, thymic ILC2 express little RANKL (receptor activator of nuclear factor kappa-B ligand) arguing that functionally, these cells provide different signals to LTi cells in the thymus. Collectively, these data reveal a dynamic switch in the ILC populations of the thymus during neonatal development.


Assuntos
Desenvolvimento Embrionário/imunologia , Linfócitos/imunologia , Timo/citologia , Timo/embriologia , Animais , Imunidade Inata/imunologia , Proteína 2 Inibidora de Diferenciação/metabolismo , Interleucina-13/biossíntese , Interleucina-5/biossíntese , Contagem de Linfócitos , Linfócitos/classificação , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Ligante RANK/biossíntese , Timo/crescimento & desenvolvimento
15.
PLoS One ; 13(6): e0198871, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29949604

RESUMO

MicroRNAs (miRNAs) have been shown to be key modulators of post-transcriptional gene silencing in many cellular processes. In previous studies designed to understand the role of miRNAs in thymic development, we globally deleted miRNA exclusively in thymic epithelial cells (TECs), which are critical in thymic selection. This resulted in the loss of stromal cells that instruct T cell lineage commitment and affect thymocyte positive selection, required for mature T cell development. Since murine miR-181 is expressed in the thymus and miR-181 deficiency disrupts thymocyte development, we first quantified and thereby demonstrated that miR181a1 and miR181b1 are expressed in purified TECs. By generating mice with TEC targeted loss of miR-181a1 and miR-181b1 expression, we observed that neither TEC cellularity nor thymocyte number nor differentiation was adversely affected. Thus, disrupted thymopoiesis in miR-181 deficient mice was not due to miR-181 loss of expression in TECs. Importantly, in mice with restricted TEC deficiency of miR-181a1 and miR-181b1, there were similar numbers of mature T cells in the periphery in regards to frequencies, differentiation, and function as compared to controls. Moreover miR-181a1 and miR-181b1 were not required for maintenance of thymus integrity over time, as thymic involution was not accelerated in gene-targeted mice. Taken together our data indicate that miR-181a1 and miR-181b1 are dispensable for TEC differentiation, their control of thymocyte development and mature T cell export to and homeostasis within the periphery.


Assuntos
Células Epiteliais/metabolismo , Regulação da Expressão Gênica , MicroRNAs/genética , Timo/citologia , Timo/crescimento & desenvolvimento , Animais , Diferenciação Celular , Células Epiteliais/citologia , Camundongos
16.
Dev Comp Immunol ; 87: 24-35, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29800626

RESUMO

Rag1 and rag2 are two closely linked recombination activating genes required for V(D)J recombination of antigen receptors in immature lymphocytes, whose expression can serve as marker to identify the lymphopoietic tissues. To study the development of lymphopoietic tissues in Chinese giant salamander (Andrias davidianus), the Chinese giant salamander rag1 and rag2 coding sequences were cloned and determined. High transcript levels of rag1 and rag2 were co-detected in the thymus before 14 months of age, whereas levels were lower in spleen, liver and kidney at all stage of development. The spatial expression patterns of rag1 and rag2 were studied in combination with igY and tcrß gene expression using in situ hybridization. Significant transcript signals for rag1, rag2, tcrß and igY were detected not only in the thymus and spleen but also the liver and kidney of juvenile and adult Chinese giant salamanders, which suggests that cells of lymphocyte lineage are present in multiple tissues of the Chinese giant salamander. This implies that lymphopoiesis may take place in these tissues. The tissue morphology of thymus suggested that the branched thymic primordium developed into mature organ with the development of thymocyte from juvenile to adult. These results not only confirm that as expected the thymus and spleen are primordial lymphopoietic tissues but also suggest that the liver and kidney provide site of lymphocyte differentiation in Chinese giant salamander.


Assuntos
Proteínas de Anfíbios/genética , Proteínas de Ligação a DNA/genética , Regulação da Expressão Gênica no Desenvolvimento , Proteínas de Homeodomínio/genética , Linfopoese/genética , Urodelos/genética , Sequência de Aminoácidos , Proteínas de Anfíbios/metabolismo , Animais , Proteínas de Ligação a DNA/classificação , Proteínas de Ligação a DNA/metabolismo , Proteínas de Homeodomínio/classificação , Proteínas de Homeodomínio/metabolismo , Hibridização In Situ , Rim/crescimento & desenvolvimento , Rim/metabolismo , Fígado/crescimento & desenvolvimento , Fígado/metabolismo , Filogenia , Homologia de Sequência de Aminoácidos , Baço/crescimento & desenvolvimento , Baço/metabolismo , Timo/crescimento & desenvolvimento , Timo/metabolismo , Urodelos/crescimento & desenvolvimento , Urodelos/metabolismo
17.
Sci Rep ; 8(1): 5605, 2018 04 04.
Artigo em Inglês | MEDLINE | ID: mdl-29618724

RESUMO

In vertebrates, multiple transcription factors (TFs) bind to gene regulatory elements (promoters, enhancers, and silencers) to execute developmental expression changes. ChIP experiments are often used to identify where TFs bind to regulatory elements in the genome, but the requirement of TF-specific antibodies hampers analyses of tens of TFs at multiple loci. Here we tested whether TF binding predictions using ATAC-seq can be used to infer the identity of TFs that bind to functionally validated enhancers of the Cd4, Cd8, and Gata3 genes in thymocytes. We performed ATAC-seq at four distinct stages of development in mouse thymus, probing the chromatin accessibility landscape in double negative (DN), double positive (DP), CD4 single positive (SP4) and CD8 SP (SP8) thymocytes. Integration of chromatin accessibility with TF motifs genome-wide allowed us to infer stage-specific occupied TF binding sites within known and potentially novel regulatory elements. Our results provide genome-wide stage-specific T cell open chromatin profiles, and allow the identification of candidate TFs that drive thymocyte differentiation at each developmental stage.


Assuntos
Timo/metabolismo , Fatores de Transcrição/metabolismo , Animais , Sequência de Bases , Antígenos CD4/genética , Antígenos CD4/metabolismo , Antígenos CD8/genética , Antígenos CD8/metabolismo , Diferenciação Celular , Cromatina/metabolismo , Elementos Facilitadores Genéticos , Fator de Transcrição GATA3/genética , Fator de Transcrição GATA3/metabolismo , Camundongos , Regiões Promotoras Genéticas , Ligação Proteica , Timo/citologia , Timo/crescimento & desenvolvimento , Fatores de Transcrição/genética
18.
Toxicology ; 396-397: 46-53, 2018 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-29428349

RESUMO

Bisphenol A (BPA) is extensively used in manufacturing of a broad range of consumer products worldwide. Due to its widespread use, human exposure to BPA is virtually ubiquitous. Broad human exposure coupled with a large scientific literature describing estrogenic activity of BPA in animals has raised public health concerns. To comprehensively evaluate the health effects of BPA exposure, a chronic toxicity study using a wide-range of BPA doses (2.5-25000 µg/kg bw/day) was conducted jointly by the NTP, thirteen NIEHS-supported grantees, and the FDA, which is called the Consortium Linking Academic and Regulatory Insights on Toxicity of BPA (CLARITY-BPA). As a participant in the CLARITY-BPA project, the objective of the current study was to evaluate the effects of chronic BPA exposure in Sprague-Dawley rats on the relative number and proportion of defined leukocyte populations in the spleen and the thymus. Toward this end, lymphoid tissues from a total of 641 rats were assayed after being continuously dosed with BPA or controls for up to one year. To comprehensively evaluate the effects of BPA on leukocyte compositions, extensive endpoints that cover major populations of leukocytes were assessed, including B cells, T cells, NK cells, granulocytes, monocytes, macrophages and dendritic cells. In total, of the 530 measurements in BPA-treated rats, 10 measurements were statistically different from vehicle controls and were mainly associated with either the macrophage or dendritic cell populations. Most, if not all, of these alterations were found to be transient with no persistent trend over the one-year time period. In addition, the observed BPA-associated alterations were mostly moderate in magnitude and not dose-dependent. Due to the aforementioned, it is unlikely that the observed BPA-mediated changes alone would adversely affect immune competence.


Assuntos
Compostos Benzidrílicos/toxicidade , Disruptores Endócrinos/toxicidade , Sistema Imunitário/efeitos dos fármacos , Leucócitos/efeitos dos fármacos , Fenóis/toxicidade , Baço/citologia , Baço/efeitos dos fármacos , Timo/citologia , Timo/efeitos dos fármacos , Animais , Relação Dose-Resposta a Droga , Feminino , Contagem de Leucócitos , Masculino , Ratos , Ratos Sprague-Dawley , Caracteres Sexuais , Timócitos/efeitos dos fármacos , Timo/crescimento & desenvolvimento
19.
Am J Pathol ; 188(4): 1043-1058, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29353058

RESUMO

Coloboma, heart defect, atresia choanae, retarded growth and development, genital hypoplasia, ear anomalies/deafness (CHARGE) syndrome is a congenital disorder affecting multiple organs and mainly caused by mutations in CHD7, a gene encoding a chromatin-remodeling protein. Immunodeficiency and reduced T cells have been noted in CHARGE syndrome. However, the mechanisms underlying T lymphopenia are largely unexplored. Herein, we observed dramatic decrease of T cells in both chd7knockdown and knockout zebrafish embryos. Unexpectedly, hematopoietic stem and progenitor cells and, particularly, lymphoid progenitor cells were increased peripherally in nonthymic areas in chd7-deficient embryos, unlikely to contribute to the T-cell decrease. Further analysis demonstrated that both the organogenesis and homing function of the thymus were seriously impaired. Chd7 might regulate thymus organogenesis through modulating the development of both neural crest cell-derived mesenchyme and pharyngeal endoderm-derived thymic epithelial cells. The expression of foxn1, a central regulator of thymic epithelium, was remarkably down-regulated in the pharyngeal region in chd7-deficient embryos. Moreover, the T-cell reduction in chd7-deficient embryos was partially rescued by overexpressing foxn1, suggesting that restoring thymic epithelium may be a potential therapeutic strategy for treating immunodeficiency in CHARGE syndrome. Collectively, the results indicated that chd7 was critical for thymic development and T-lymphopenia in CHARGE syndrome may be mainly attributed to the defects of thymic organogenesis. The current finding may benefit the diagnosis and therapy of T lymphopenia and immunodeficiency in CHARGE syndrome.


Assuntos
DNA Helicases/metabolismo , Proteínas de Ligação a DNA/metabolismo , Organogênese , Linfócitos T/citologia , Timo/citologia , Timo/crescimento & desenvolvimento , Proteínas de Peixe-Zebra/metabolismo , Peixe-Zebra/metabolismo , Animais , Animais Geneticamente Modificados , Apoptose/efeitos dos fármacos , Sequência de Bases , Proteínas Morfogenéticas Ósseas/metabolismo , Região Branquial/efeitos dos fármacos , Região Branquial/embriologia , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Quimiocinas/metabolismo , DNA Helicases/deficiência , Proteínas de Ligação a DNA/deficiência , Embrião não Mamífero/metabolismo , Células Epiteliais/metabolismo , Fatores de Transcrição Forkhead/metabolismo , Células-Tronco Hematopoéticas/metabolismo , Morfolinos/farmacologia , Mutação/genética , Crista Neural/patologia , Fenótipo , Transdução de Sinais , Peixe-Zebra/embriologia , Proteínas de Peixe-Zebra/deficiência
20.
Horm Metab Res ; 49(11): 892-898, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-29136677

RESUMO

Type 1 diabetes (T1D) during pregnancy possibly affects the development of the thymus and the maturation of the immune system in the offspring. The aim of the ImmunDiabRisk study was to investigate thymus growth and maternal and fetal immune responses in pregnancies with and without T1D. The thymus circumferences of the fetuses of pregnant women with T1D (n=49) and without diabetes (n=59) were measured using ultrasound around the 29th gestational week and standardized for gestational age. Simultaneously, the frequencies and total numbers of cell markers were analyzed by flow cytometry in maternal peripheral blood, and at birth in umbilical cord blood. The standardized circumference of the thymus was similar in fetuses of mothers with and without T1D (p=0.26). We observed higher numbers of FOXP3 Tregs, memory Tregs, erythrocytes, and lymphocytes in the cord blood from T1D pregnancies (p=0.01, p=0.002, p=0.002 and p=0.02, respectively). The frequencies of CD4+/CD8+ T cells correlated positively in maternal blood and umbilical cord blood of mother-child pairs, as did the levels of neutrophils (Spearman's correlation coefficient r=0.43, p=0.02 for CD4+/CD8+ cells; r=0.46, p=0.03 for neutrophils), while no significant correlations were observed between thymus circumference and any cell markers in the child. Parts of the prenatal immune system seem to develop differently in the offspring of mothers with and without T1D. The correlation of Tregs between maternal blood and cord blood may indicate a significant cross-talk between the maternal and fetal immune system.


Assuntos
Diabetes Gestacional/imunologia , Feto/imunologia , Imunidade , Timo/crescimento & desenvolvimento , Peso ao Nascer , Células Sanguíneas/metabolismo , Diabetes Mellitus Tipo 1/imunologia , Feminino , Sangue Fetal/metabolismo , Idade Gestacional , Humanos , Recém-Nascido , Mães , Tamanho do Órgão , Gravidez , Estatísticas não Paramétricas
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA