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1.
Immunogenetics ; 71(7): 489-499, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31297569

RESUMO

Epigenetic modifications have been shown to be important for immune cell differentiation by regulating gene transcription. However, the role and mechanism of histone methylation in the development and differentiation of iNKT cells in rheumatoid arthritis (RA) mice have yet to be deciphered. The DBA/1 mouse RA model was established by using a modified GPI mixed peptide. We demonstrated that total peripheral blood, thymus, and spleen iNKT cells in RA mice decreased significantly, while iNKT1 in the thymus and spleen was increased significantly. PLZF protein and PLZF mRNA levels were significantly decreased in thymus DP T cells, while T-bet protein and mRNA were significantly increased in thymus iNKT cells. We found a marked accumulation in H3K27me3 around the promoter regions of the signature gene Zbtb16 in RA mice thymus DP T cells, and an accumulation of H3K4me3 around the promoters of the Tbx21 gene in iNKT cells. The expression levels of UTX in the thymus of RA mice were significantly reduced. The changes in the above indicators were particularly significant in the progressive phase of inflammation (11 days after modeling) and the peak phase of inflammation (14 days after modeling) in RA mice. Developmental and differentiation defects of iNKT cells in RA mice were associated with abnormal methylation levels (H3K27me3 and H3K4me3) in the promoters of key genes Zbtb16 (encoding PLZF) and Tbx21 (encoding T-bet). Decreased UTX of thymus histone demethylase levels resulted in the accumulation of H3K27me3 modification.


Assuntos
Artrite Reumatoide/patologia , Lisina/metabolismo , Células T Matadoras Naturais/patologia , Regiões Promotoras Genéticas , Timo/fisiologia , Animais , Artrite Experimental/patologia , Diferenciação Celular , Epigênese Genética , Regulação da Expressão Gênica , Histona Desmetilases/genética , Histona Desmetilases/metabolismo , Metilação , Camundongos Endogâmicos DBA , Proteína com Dedos de Zinco da Leucemia Promielocítica/genética , Proteína com Dedos de Zinco da Leucemia Promielocítica/metabolismo , Baço/patologia , Proteínas com Domínio T/genética , Proteínas com Domínio T/metabolismo
2.
Braz J Med Biol Res ; 52(7): e8292, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31241713

RESUMO

The thymus is a primary lymphoid organ responsible for the maturation of T cells as well as the immunological central tolerance. It is in the antenatal period and infancy that it plays its major role. In clinical practice, T cell receptor excision circles (TRECs) are considered a direct and reliable measure of the thymic function. TRECs are a by-product of DNA formation in gene rearrangement of T cell receptors. They are stable and they do not duplicate during mitosis, representing the recent emigrant T cells from the thymus. Despite their importance, TRECs have been neglected by physicians and there is a lack of data regarding thymic function during infancy of healthy children. In order to evaluate thymic function in the first years of life, we propose measuring TRECs as a valuable tool. One hundred and three blood samples from children and adolescents between 3 months and 20 years of age were analyzed. The mean TRECs count was 136.77±96.7 copies of TRECs/µL of DNA. The individuals between 0 and 5 years of age had significantly higher TRECs values than those between 10 and 20 years of age. No significant difference was observed in TRECs values among age groups below 5 years of age. An inverse correlation between TRECs and age was found (r=0.3 P=0.003). These data highlight and validate the evidence of decreased thymus function with age, even during infancy. Awareness should be raised with this important albeit ignored organ.


Assuntos
Receptores de Antígenos de Linfócitos T/fisiologia , Timo/fisiologia , Adolescente , Biomarcadores/sangue , Criança , Pré-Escolar , Rearranjo Gênico do Linfócito T , Humanos , Lactente , Valores de Referência , Reprodutibilidade dos Testes , Timo/citologia , Adulto Jovem
3.
Thorac Surg Clin ; 29(2): 123-131, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30927993

RESUMO

The thymus is a primary lymphoid organ essential for the development of T lymphocytes, which orchestrate adaptive immune responses. T-cell development in the thymus is spatially regulated; key checkpoints in T-cell maturation and selection occur in cortical and medullary regions to eliminate self-reactive T cells, establish central tolerance, and export naïve T cells to the periphery with the potential to recognize diverse pathogens. Thymic output is also temporally regulated due to age-related involution of the thymus accompanied by loss of epithelial cells. This review discusses the structural and age-related control of thymus function in humans.


Assuntos
Timo/imunologia , Timo/fisiologia , Envelhecimento/imunologia , Envelhecimento/fisiologia , Homeostase/fisiologia , Humanos , Sistema Imunitário/fisiologia , Linfócitos T/fisiologia , Timo/embriologia
4.
Cell Tissue Res ; 376(1): 19-24, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30762129

RESUMO

The thymus is a primary lymphoid organ where T lymphocyte proliferation and selection takes place. The different subsets of lymphocytes leave the thymus as recent thymic emigrants. Peripheral dendritic cells migrate to the thymus. In addition to the homing of hematopoietic progenitor cells to the thymus, there is evidence for lymphocyte entry from peripheral lymphoid tissues mainly into the medulla. The entry sites are the venules in the medullary part near to the cortex with a higher endothelium. Furthermore, there are also B lymphocytes in the thymus. The thymus is not only a primary lymphoid organ but is well integrated in lymphocyte traffic as shown in several different species.


Assuntos
Movimento Celular , Linfócitos , Timo/fisiologia , Animais , Células Dendríticas/citologia , Células Dendríticas/imunologia , Células-Tronco Hematopoéticas/citologia , Células-Tronco Hematopoéticas/imunologia , Humanos , Linfócitos/citologia , Linfócitos/imunologia
5.
Bull Exp Biol Med ; 166(3): 409-412, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30627895

RESUMO

Activity of apoptosis in the thymus, liver, and kidneys on days 20, 22, 35, 50, 80, 110, and 140 of ontogeny was studied in the experiments on rats using the alkaline gel electrophoresis and flow cytofluorometry. Changes in apoptosis intensity depended on animal age. The maximum level of this parameter was observed on day 20 of ontogeny with the following reduction in this parameter to the minimum value on days 35-50. Then it gradually increased up to relatively high levels on day 110 and significantly reduced by day 140.


Assuntos
Envelhecimento/fisiologia , Apoptose/fisiologia , Células Eucarióticas/fisiologia , Rim/fisiologia , Fígado/fisiologia , Timo/fisiologia , Animais , Animais Recém-Nascidos , Peso Corporal , Células Eucarióticas/citologia , Feminino , Feto , Rim/citologia , Cinética , Fígado/citologia , Masculino , Gravidez , Ratos , Ratos Wistar , Fatores Sexuais , Maturidade Sexual/fisiologia , Timo/citologia
6.
Immunobiology ; 224(1): 133-141, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30348458

RESUMO

The present study was undertaken to investigate whether or not chronic stress effect and its reversibility on lymphoid organs is duration dependent. Male rats were exposed to restraint (1 h) followed by a gap of 4 h to forced swimming exercise (15 min) daily for 2, 4 and 8 weeks. After each exposure period, rats were allowed to recover for 6 weeks. Stress exposure resulted in duration dependent decreases in weight of thymus and axillary lymph nodes, lymphocyte counts of spleen, thymus and axillary lymph nodes and number of islets of white pulp of spleen and increases in apoptotic index of splenocytes, thymocytes and lymphocytes of axillary lymph nodes. All the parameters of lymphoid organs studied showed significant alterations in 2 weeks of stress exposure indicated their sensitivity to stress effects in short term exposure and thymus was the most sensitive organ among all. The alterations in all the parameters of spleen and majority of parameters of thymus and axillary lymph nodes returned to control level in recovery group rats of 2 and 4 weeks exposure but not in that of 8 weeks exposure. The present study for the first time reveal that severity of stress effects on lymphoid organs increases with increasing duration of exposure and shorter the exposure period faster the recovery. In addition, an in vitro study showed that corticosterone caused apoptosis of thymocytes, splenocytes and lymphocytes of axillary lymph nodes in dose dependent manner. Thus corticosterone induced death of cells of lymphoid organs under stress is the major cause of involution of lymphoid organs.


Assuntos
Linfonodos/fisiologia , Linfócitos/fisiologia , Tecido Linfoide/fisiologia , Estresse Fisiológico/imunologia , Timócitos/fisiologia , Timo/fisiologia , Animais , Apoptose , Células Cultivadas , Doença Crônica , Corticosterona/farmacologia , Modelos Animais de Doenças , Humanos , Masculino , Ratos , Ratos Endogâmicos , Restrição Física
7.
Immunol Cell Biol ; 97(2): 190-202, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30291723

RESUMO

Mucosal-associated invariant T (MAIT) cells constitute a major fraction of innate-like T cells in humans with critical roles in defense against microbial pathogens and in maintaining mucosal integrity. However, the molecular mechanisms underlying MAIT cell development remain largely elusive. Here we investigated the role of miR-181a/b-1, a pair of microRNAs that serve as rheostat of TCR signal strength, in this process. Loss of miR-181a/b-1 in mice resulted in a profound arrest in early MAIT cell development. As a consequence, in the absence of miR-181a/b-1, thymic MAIT cells failed to acquire functional maturity based on expression of transcription factors PLZF, T-bet and RORγt. Temporal analysis of development using a molecular timer in combination with loss of miR-181a/b-1 revealed that MAIT cells complete functional maturation in the periphery and indicates that functionally mature MAIT cells in the thymus are long-term resident cells. Thus, our study provides insight into the dynamics of MAIT cell development in vivo. Of note, deletion of miR-181a/b-1 alone completely mirrored loss of all miRNAs.


Assuntos
MicroRNAs/metabolismo , Células T Invariáveis Associadas à Mucosa , Timo/fisiologia , Animais , Diferenciação Celular/genética , Diferenciação Celular/imunologia , Camundongos , MicroRNAs/genética , Células T Invariáveis Associadas à Mucosa/citologia , Células T Invariáveis Associadas à Mucosa/metabolismo , Timo/citologia
8.
Int Immunopharmacol ; 67: 194-201, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30557822

RESUMO

Defect of thymus results in poor posttransplant immune recovery and dysfunction of immune tolerance after allogeneic hematopoietic cell transplants (allo-HCT). Improving thymus regeneration represents a potential strategy to accelerate recovery of T-cell immunity. IL-22 was reported to mediate thymus regeneration after injury. In this study, we found donor T-cell is a major source of IL-22 in allotransplant recipient. Through applying IL-22 knock out (IL-22KO) mice in allo-HCT, we found donor T-cell derived IL-22 promotes thymus regeneration in association with increased level of intra-thymic IL-22. IL-22KO T-cell-transplanted recipients show deficient thymus recovery which is reversed by injection of exogenous IL-22. T-cell derived IL-22 promotes proliferation of thymic epithelial cells (TECs) in vitro. In addition, donor T-cell derived IL-22 increases expression level of Aire in the thymus and decreases skin chronic graft-versus-host disease (GVHD). Furthermore, short-term use of exogenous IL-22 posttransplant accelerates recovery of thymus without increasing severity of acute GVHD. Our data indicate that cross-talk between T-cell and TECs is an important mechanism to mediate reconstitution of T-cell immunity after allo-HCT.


Assuntos
Transplante de Medula Óssea , Doença Enxerto-Hospedeiro/terapia , Interleucinas/farmacologia , Linfócitos T/metabolismo , Timo/fisiologia , Animais , Linhagem Celular , Sobrevivência Celular , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/fisiologia , Regulação da Expressão Gênica , Interleucinas/genética , Interleucinas/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Timo/efeitos dos fármacos , Doadores de Tecidos , Transplante Homólogo
9.
Acta Microbiol Immunol Hung ; 66(1): 1-17, 2019 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-29968490

RESUMO

The role of immune system is to protect the organism from the not built-in program-like alterations inside and against the agents penetrating from outside (bacteria, viruses, and protozoa). These functions were developed and formed during the evolution. Considering these functions, the immune system promotes the lengthening of lifespan and helps longevity. However, some immune functions have been conveyed by men to medical tools (e.g., pharmaceuticals, antibiotics, and prevention), especially in our modern age, which help the struggle against microbes, but evolutionarily weaken the immune system. Aging is a gradual slow attrition by autoimmunity, directed by the thymus and regulated by the central nervous system and pineal gland. Considering this, thymus could be a pacemaker of aging. The remodeling of the immune system, which can be observed in elderly people and centenarians, is probably not a cause of aging, but a consequence of it, which helps to suit immunity to the requirements. Oxidative stress also helps the attrition of the immune cells and antioxidants help to prolong lifespan. There are gender differences in the aging of the immune system as well as in the longevity. There is an advantage for women in both cases. This can be explained by hormonal differences (estrogens positively influences both processes); however, social factors are also not excluded. The endocrine disruptor chemicals act similar to estrogens, like stimulating or suppressing immunity and provoking autoimmunity; however, their role in longevity is controversial. There are some drugs (rapamycin, metformin, and selegiline) and antioxidants (as vitamins C and E) that prolong lifespan and also improve immunity. It is difficult to declare that longevity is exclusively dependent on the state of the immune system; however, there is a parallelism between the state of immune system and lifespan. It seems likely that there is not a real decline of immunity during aging, but there is a remodeling of the system according to the claims of senescence. This is manifested in the remaining (sometimes stronger) function of memory cells in contrast to the production and number of the new antigen-reactive naive T-cells.


Assuntos
Envelhecimento , Sistema Imunitário/fisiologia , Longevidade , Humanos , Fatores Sexuais , Timo/fisiologia
10.
Immunol Cell Biol ; 97(3): 299-304, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30565320

RESUMO

Barely 60 years ago, the thymus was considered to be a vestigial organ with no known function or just a graveyard for dying lymphocytes. Now, the thymus and its cells cover a vast area of immunology, genetics and epigenetics relating to medicine, including inflammation, infection, vaccination, dysbiosis, immunodeficiency, allergy, autoimmunity, transplantation, tissue repair, pregnancy and cancer. New technology and approaches, now becoming available, will lead to a much deeper understanding of many of these conditions. Hence, the thymus and its cells will be occupying researchers and clinicians for decades to come.


Assuntos
Imunidade , Timo/fisiologia , Alergia e Imunologia , Animais , História do Século XX , Humanos , Linfócitos/citologia , Linfócitos/imunologia , Linfócitos/metabolismo , Pesquisa , Timo/citologia
11.
J Immunol ; 201(11): 3244-3257, 2018 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-30389776

RESUMO

Medullary thymic epithelial cells (mTECs), which express a wide range of tissue-restricted Ags (TRAs), contribute to the establishment of self-tolerance by eliminating autoreactive T cells and/or inducing regulatory T cells. Aire controls a diverse set of TRAs within Aire-expressing cells by employing various transcriptional pathways. As Aire has a profound effect on transcriptomes of mTECs, including TRAs not only at the single-cell but also the population level, we suspected that Aire (Aire+ mTECs) might control the cellular composition of the thymic microenvironment. In this study, we confirmed that this is indeed the case by identifying a novel mTEC subset expressing Ly-6 family protein whose production was defective in Aire-deficient thymi. Reaggregated thymic organ culture experiments demonstrated that Aire did not induce the expression of Ly-6C/Ly-6G molecules from mTECs as Aire-dependent TRAs in a cell-intrinsic manner. Instead, Aire+ mTECs functioned in trans to maintain Ly-6C/Ly-6G+ mTECs. Thus, Aire not only controls TRA expression transcriptionally within the cell but also controls the overall composition of mTECs in a cell-extrinsic manner, thereby regulating the transcriptome from mTECs on a global scale.


Assuntos
Células Epiteliais/patologia , Timo/fisiologia , Fatores de Transcrição/metabolismo , Animais , Antígenos Ly/metabolismo , Células Cultivadas , Microambiente Celular , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Técnicas de Cultura de Órgãos , Fatores de Transcrição/genética , Ativação Transcricional
12.
Front Immunol ; 9: 2497, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30455689

RESUMO

Development of T cells in the thymus is tightly controlled to continually produce functional, but not autoreactive, T cells. miRNAs provide a layer of post-transcriptional gene regulation to this process, but the role of many individual miRNAs in T-cell development remains unclear. miR-21 is prominently expressed in immature thymocytes followed by a steep decline in more mature cells. We hypothesized that such a dynamic expression was indicative of a regulatory function in intrathymic T-cell development. To test this hypothesis, we analyzed T-cell development in miR-21-deficient mice at steady state and under competitive conditions in mixed bone-marrow chimeras. We complemented analysis of knock-out animals by employing over-expression in vivo. Finally, we assessed miR-21 function in negative selection in vivo as well as differentiation in co-cultures. Together, these experiments revealed that miR-21 is largely dispensable for physiologic T-cell development. Given that miR-21 has been implicated in regulation of cellular stress responses, we assessed a potential role of miR-21 in endogenous regeneration of the thymus after sublethal irradiation. Again, miR-21 was completely dispensable in this process. We concluded that, despite prominent and highly dynamic expression in thymocytes, miR-21 expression was not required for physiologic T-cell development or endogenous regeneration.


Assuntos
MicroRNAs/genética , Linfócitos T/fisiologia , Timócitos/fisiologia , Timo/fisiologia , Animais , Medula Óssea , Diferenciação Celular , Células Cultivadas , Quimera , Seleção Clonal Mediada por Antígeno , Técnicas de Cocultura , Regulação da Expressão Gênica , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout
13.
Int J Med Sci ; 15(13): 1555-1563, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30443178

RESUMO

Atherosclerosis is one kind of chronic inflammatory disease, in which multiple types of immune cells or factors are involved. Data from experimental and clinical studies on atherosclerosis have confirmed the key roles of immune cells and inflammation in such process. The thymus as a key organ in T lymphocyte ontogenesis has an important role in optimizing immune system function throughout the life, and dysfunction of thymus has been proved to be associated with severity of atherosclerosis. Based on previous research, we begin with the hypothesis that low density lipoprotein or cholesterol reduces the expression of the thymus transcription factor Foxn1 via low density lipoprotein receptors on the membrane surface and low density lipoprotein receptor related proteins on the cell surface, which cause the thymus function decline or degradation. The imbalance of T cell subgroups and the decrease of naive T cells due to thymus dysfunction cause the increase or decrease in the secretion of various inflammatory factors, which in turn aggravates or inhibits atherosclerosis progression and cardiovascular events. Hence, thymus may be the pivotal role in coronary heart disease mediated by atherosclerosis and cardiovascular events and it can imply a novel treatment strategy for the clinical management of patients with atherosclerosis in addition to different commercial drugs. Modulation of immune system by inducing thymus function may be a therapeutic approach for the prevention of atherosclerosis. Purpose of this review is to summarize and discuss the recent advances about the impact of thymus function on atherosclerosis by the data from animal or human studies and the potential mechanisms.


Assuntos
Aterosclerose/metabolismo , Inflamação/metabolismo , Timo/metabolismo , Envelhecimento/genética , Envelhecimento/fisiologia , Animais , Aterosclerose/imunologia , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/metabolismo , Humanos , Inflamação/imunologia , Timo/fisiologia
14.
J Immunol ; 201(11): 3320-3328, 2018 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-30373854

RESUMO

Age-related thymic involution is characterized by a decrease in thymic epithelial cell (TEC) number and function parallel to a disruption in their spatial organization, resulting in defective thymocyte development and proliferation as well as peripheral T cell dysfunction. Deficiency of Klotho, an antiaging gene and modifier of fibroblast growth factor signaling, causes premature aging. To investigate the role of Klotho in accelerated age-dependent thymic involution, we conducted a comprehensive analysis of thymopoiesis and peripheral T cell homeostasis using Klotho-deficient (Kl/Kl) mice. At 8 wk of age, Kl/Kl mice displayed a severe reduction in the number of thymocytes (10-100-fold reduction), especially CD4 and CD8 double-positive cells, and a reduction of both cortical and medullary TECs. To address a cell-autonomous role for Klotho in TEC biology, we implanted neonatal thymi from Klotho-deficient and -sufficient mice into athymic hosts. Kl/Kl thymus grafts supported thymopoiesis equivalently to Klotho-sufficient thymus transplants, indicating that Klotho is not intrinsically essential for TEC support of thymopoiesis. Moreover, lethally irradiated hosts given Kl/Kl or wild-type bone marrow had normal thymocyte development and comparably reconstituted T cells, indicating that Klotho is not inherently essential for peripheral T cell reconstitution. Because Kl/Kl mice have higher levels of serum phosphorus, calcium, and vitamin D, we evaluated thymus function in Kl/Kl mice fed with a vitamin D-deprived diet. We observed that a vitamin D-deprived diet abrogated thymic involution and T cell lymphopenia in 8-wk-old Kl/Kl mice. Taken together, our data suggest that Klotho deficiency causes thymic involution via systemic effects that include high active vitamin D levels.


Assuntos
Senilidade Prematura/genética , Envelhecimento/fisiologia , Células Epiteliais/fisiologia , Glucuronidase/metabolismo , Linfócitos T/fisiologia , Timócitos/fisiologia , Timo/fisiologia , Transferência Adotiva , Animais , Células Cultivadas , Dietoterapia , Fatores de Crescimento de Fibroblastos/metabolismo , Glucuronidase/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Timo/transplante , Transplante , Vitamina D/metabolismo
15.
J Immunol ; 201(8): 2215-2219, 2018 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-30209190

RESUMO

Murine Foxp3+ regulatory T cells (Tregs) differentiated in vitro (induced Tregs [iTregs]) in the presence of anti-inflammatory cytokine TGF-ß rely predominantly upon lipid oxidation to fuel mitochondrial oxidative phosphorylation. Foxp3 expression underlies this metabolic preference, as it suppresses glycolysis and drives oxidative phosphorylation. In this study, we show that in contrast to iTregs, thymic-derived Tregs (tTregs), engage in glycolysis and glutaminolysis at levels comparable to effector T cells despite maintained Foxp3 expression. Interestingly, exposure of tTregs to the anti-inflammatory cytokine TGF-ß represses PI3K-mediated mTOR signaling, inhibits glucose transporter and Hk2 expression, and reprograms their metabolism to favor oxidative phosphorylation. Conversely, replicating the effects of inflammation via elevation of PI3K signaling has minimal effects on tTregs but dramatically enhances the glycolysis of normally oxidative iTregs, resulting in reduction of Foxp3 expression. Collectively, these findings suggest both extrinsic and intrinsic factors govern the unique metabolic signature of Treg subsets.


Assuntos
Fatores de Transcrição Forkhead/metabolismo , Fosfatidilinositol 3-Quinase/metabolismo , Subpopulações de Linfócitos T/imunologia , Linfócitos T Reguladores/imunologia , Timo/fisiologia , Fator de Crescimento Transformador beta/metabolismo , Animais , Diferenciação Celular , Células Cultivadas , Reprogramação Celular , Fatores de Transcrição Forkhead/genética , Glicólise , Imunomodulação , Ativação Linfocitária , Camundongos , Camundongos Transgênicos , Fosforilação Oxidativa , Transdução de Sinais , Serina-Treonina Quinases TOR/metabolismo
16.
Nat Commun ; 9(1): 3594, 2018 09 05.
Artigo em Inglês | MEDLINE | ID: mdl-30185805

RESUMO

The inheritance of gene expression patterns is dependent on epigenetic regulation, but the establishment and maintenance of epigenetic landscapes during T cell differentiation are incompletely understood. Here we show that two stage-specific Cd4 cis-elements, the previously characterized enhancer E4p and a novel enhancer E4m, coordinately promote Cd4 transcription in mature thymic MHC-II-specific T cells, in part through the canonical Wnt pathway. Specifically, E4p licenses E4m to orchestrate DNA demethylation by TET1 and TET3, which in turn poises the Cd4 locus for transcription in peripheral T cells. Cd4 locus demethylation is important for subsequent Cd4 transcription in activated peripheral T cells wherein these cis-elements become dispensable. By contrast, in developing thymocytes the loss of TET1/3 does not affect Cd4 transcription, highlighting an uncoupled event between transcription and epigenetic modifications. Together our findings reveal an important function for thymic cis-elements in governing gene expression in the periphery via a heritable epigenetic mechanism.


Assuntos
Antígenos CD4/genética , Linfócitos T CD4-Positivos/fisiologia , Elementos Facilitadores Genéticos/fisiologia , Epigênese Genética/fisiologia , Regulação da Expressão Gênica/fisiologia , Animais , Antígenos CD4/metabolismo , Diferenciação Celular/genética , Quimera , Desmetilação do DNA , Metilação de DNA/fisiologia , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Feminino , Técnicas de Inativação de Genes , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/metabolismo , Timo/citologia , Timo/fisiologia
17.
J Immunol ; 201(7): 1975-1983, 2018 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-30150284

RESUMO

Cancer-initiating/sustaining stem cell subsets (CSCs) have the potential to regenerate cancer cell populations and are resistant to routine therapeutic strategies, thus attracting much attention in anticancer research. In this study, an innovative framework of endogenous microenvironment-renewal for addressing such a dilemma has been just developed. CSCs in three-dimensional multipotent spheroid-engineered biologics were prepared with 150 Gy radiation and inoculated into 15-mo-old BALB/c and C57BL/6 mice bearing diverse advanced tumors covering Mammary 4T1, liver Hepa, lung LL/2, and colon C26 tumors and distant metastases. Subsequently, the systematic microenvironment of tumor-bearing hosts was rapidly remodeled to resettle thymic cortex and medulla rudiment as an endogenous foxn1-thymosin reprogramming TCR-repertoire for resetting MHC-unrestricted multifunction renewal. Postrenewal Vγ4γδT-subsets would bind and lead migrating CSCs into apoptosis. Moreover, TCR repertoire multifunction renewal could reverse tumor metastases from tumoricidal resistance into eventual regression as a blockade of cancer-sustaining Bmi-1/Nanog-Oct4-Sox2 renewal loop with sequent multivalent depletion of both migrating/in situ CSCs and non-stem terminal cancer cell subsets. This study represents a promising start to set up a generalizable strategy of three-dimensional biologics evoking an endogenous integral microenvironment into pluripotent renewal versus advanced cancer.


Assuntos
Terapia Biológica , Técnicas de Reprogramação Celular , Células-Tronco Multipotentes/fisiologia , Neoplasias Experimentais/imunologia , Células-Tronco Neoplásicas/fisiologia , Linfócitos T/imunologia , Timo/fisiologia , Animais , Apoptose , Técnicas de Cultura de Células , Diferenciação Celular , Linhagem Celular Tumoral , Autorrenovação Celular , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/metabolismo , Regulação Neoplásica da Expressão Gênica , Imunidade Celular , Imunização , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Metástase Neoplásica , Neoplasias Experimentais/terapia , Radiação , Receptores de Antígenos de Linfócitos T gama-delta/metabolismo , Timosina/genética , Timosina/metabolismo , Engenharia Tecidual , Microambiente Tumoral
18.
Domest Anim Endocrinol ; 65: 101-108, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30099262

RESUMO

Glucocorticoids (GCs) are illegally used as growth promoters in cattle, and the analytical methods officially applied most likely underestimate the precise frequency of the abuse. As a side effect, the administration of GCs causes fat infiltration, apoptosis, and atrophy of the thymus. However, gross and histological observations carried out previously showed that the thymus preserves an intrinsic ability to regenerate. The aim of this work was to study the transcriptional effects of GCs on genes likely involved in regeneration of the epithelial cell network in the cervical and thoracic thymus of beef cattle treated with dexamethasone (DEX) or prednisolone (PRD) in comparison with a control group. Moreover, the ratio of bax/bcl2 genes was examined to verify a possible antiapoptotic activity occurring at the same time. In the cervical thymus, DEX administration increased the gene expression of c-myc (P < 0.01), tcf3 (P < 0.05), tp63 (P < 0.01), and keratin 5 (krt5; P < 0.01). In the thoracic thymus of DEX-treated cattle, the gene expression of tcf3 (P < 0.01), tp63 (P < 0.01), and krt5 (P < 0.05) was increased. These results suggested that thymic regeneration is underway in the DEX-treated animals. However, the bax/bcl2 ratio was decreased in both cervical and thoracic thymus of DEX-treated cattle (P < 0.01 and P < 0.05, respectively), showing an antiapoptotic effect through the mitochondrial pathway. Conversely, PRD administration caused no change in the expression of all considered genes. These results sustain the hypothesis that regeneration occurs in the thymus parenchyma 6 d after the DEX treatment was discontinued. This hypothesis is also supported by the absence of alterations in the thymus of PRD-treated beef cattle. Indeed, previous studies showed the inability of PRD to induce macroscopic and microscopic lesions in the thymus. Therefore, in this context, it is not surprising that PRD induced no alteration of genes involved in the regeneration pathway.


Assuntos
Glucocorticoides/administração & dosagem , Regeneração/genética , Timo/fisiologia , Transcriptoma/efeitos dos fármacos , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Bovinos , Dexametasona/administração & dosagem , Expressão Gênica/efeitos dos fármacos , Genes myc/genética , Queratina-5/genética , Prednisolona/administração & dosagem , RNA Mensageiro/análise , Carne Vermelha , Regeneração/efeitos dos fármacos , Fatores de Transcrição/genética , Proteínas Supressoras de Tumor
19.
Sci Immunol ; 3(25)2018 07 06.
Artigo em Inglês | MEDLINE | ID: mdl-29980617

RESUMO

The interaction between extrinsic factors and intrinsic signal strength governs thymocyte development, but the mechanisms linking them remain elusive. We report that mechanistic target of rapamycin complex 1 (mTORC1) couples microenvironmental cues with metabolic programs to orchestrate the reciprocal development of two fundamentally distinct T cell lineages, the αß and γδ T cells. Developing thymocytes dynamically engage metabolic programs including glycolysis and oxidative phosphorylation, as well as mTORC1 signaling. Loss of RAPTOR-mediated mTORC1 activity impairs the development of αß T cells but promotes γδ T cell generation, associated with disrupted metabolic remodeling of oxidative and glycolytic metabolism. Mechanistically, we identify mTORC1-dependent control of reactive oxygen species production as a key metabolic signal in mediating αß and γδ T cell development, and perturbation of redox homeostasis impinges upon thymocyte fate decisions and mTORC1-associated phenotypes. Furthermore, single-cell RNA sequencing and genetic dissection reveal that mTORC1 links developmental signals from T cell receptors and NOTCH to coordinate metabolic activity and signal strength. Our results establish mTORC1-driven metabolic signaling as a decisive factor for reciprocal αß and γδ T cell development and provide insight into metabolic control of cell signaling and fate decisions.


Assuntos
Diferenciação Celular/fisiologia , Alvo Mecanístico do Complexo 1 de Rapamicina/fisiologia , Subpopulações de Linfócitos T/fisiologia , Animais , Linhagem da Célula , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Proteínas Proto-Oncogênicas c-myc/fisiologia , Espécies Reativas de Oxigênio/metabolismo , Proteína Regulatória Associada a mTOR/fisiologia , Transdução de Sinais , Timo/fisiologia
20.
IUBMB Life ; 70(7): 678-690, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29727505

RESUMO

MicroRNAs (miRNAs) play key roles in the regulation of gene expression during multiple physiological processes, including early development, differentiation, and ageing. However, their involvement in age-related thymic involution is not clear. In this study, we profiled the global transcriptome and miRNAome of thymic epithelial cells in 1- and 3-month-old male and female mice, and predicted the possible transcription factors and target genes of the four most significantly differentially expressed miRNAs (DEMs) (miR-183-5p, miR-199b-5p, miR-205-5p, and miR-200b-3p) by performing bioinformatics analyses. We also evaluated the relationships between the significantly DEMs and mRNAs. We performed quantitative polymerase chain reaction to confirm the changes in the expression of the miRNAs and their predicted target genes. We found that miR-183-5p, miR-199b-5p, miR-205-5p, and miR-200b-3p can be used as a biomarker group for mouse thymus development and involution. In addition, the predicted target genes (Ptpn4, Slc2a9, Pkib, Pecam1, and Prkdc), which were identified by mRNA sequencing analysis, were mainly involved in growth, development, and accelerated senescence. In conclusion, miRNAs and their predicted target genes likely play important roles in thymus development and involution. To the best of our knowledge, this is the first study to systematically analyze the relevance of miRNAs and their targets by mRNA sequencing in mouse thymic epithelial cells. © 2018 IUBMB Life, 70(7):678-690, 2018.


Assuntos
Envelhecimento/genética , Células Epiteliais/fisiologia , MicroRNAs/genética , RNA Mensageiro/genética , Timo/citologia , Animais , Feminino , Redes Reguladoras de Genes , Sequenciamento de Nucleotídeos em Larga Escala , Masculino , Camundongos Endogâmicos BALB C , Mapas de Interação de Proteínas/genética , Reação em Cadeia da Polimerase em Tempo Real , Reprodutibilidade dos Testes , Timo/fisiologia , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
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