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1.
Int J Biol Sci ; 18(2): 617-636, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35002513

RESUMEN

Among numerous studies on coronavirus 2019 (COVID-19), we noted that the infection and mortality rates of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) increased with age and that fetuses known to be particularly susceptible to infection were better protected despite various mutations. Hence, we established the hypothesis that a new immune system exists that forms before birth and decreases with aging. Methods: To prove this hypothesis, we established new ex-vivo culture conditions simulating the critical environmental factors of fetal stem cells (FSCs) in early pregnancy. Then, we analyzed the components from FSCs cultivated newly developed ex-vivo culture conditions and compared them from FSCs cultured in a normal condition. Results: We demonstrated that immunoglobulin M (IgM), a natural antibody (NAb) produced only in early B-1 cells, immunoglobulins (Igs) including IgG3, which has a wide range of antigen-binding capacity and affinity, complement proteins, and antiviral proteins are induced in FSCs only cultured in newly developed ex-vivo culture conditions. Particularly we confirmed that their extracellular vesicles (EVs) contained NAbs, Igs, various complement proteins, and antiviral proteins, as well as human leukocyte antigen G (HLA-G), responsible for immune tolerance. Conclusion: Our results suggest that FSCs in early pregnancy can form an independent immune system responding to unlearned antigens as a self-defense mechanism before establishing mature immune systems. Moreover, we propose the possibility of new solutions to cope with various infectious diseases based on the factors in NAbs-containing EVs, especially not causing unnecessary immune reaction due to HLA-G.


Asunto(s)
Envejecimiento/inmunología , COVID-19/inmunología , Células Madre Fetales/fisiología , Inmunidad/fisiología , SARS-CoV-2 , Afinidad de Anticuerpos , Antígenos Virales , Agentes Antiglaucoma , Proteínas del Sistema Complemento , Femenino , Células Madre Fetales/virología , Regulación del Desarrollo de la Expresión Génica/inmunología , Humanos , Inmunoglobulinas/metabolismo , Embarazo
2.
FASEB J ; 35(8): e21758, 2021 08.
Artículo en Inglés | MEDLINE | ID: mdl-34245611

RESUMEN

After birth, the alveolar epithelium is exposed to environmental pathogens and high O2 tensions. The alveolar type II cells may protect this epithelium through surfactant production. Surfactant protein, SP-A, an immune modulator, is developmentally upregulated in fetal lung with surfactant phospholipid synthesis. Herein, we observed that the redox-regulated transcription factor, NRF2, and co-regulated C/EBPß and PPARγ, were markedly induced during cAMP-mediated differentiation of cultured human fetal lung (HFL) epithelial cells. This occurred with enhanced expression of immune modulators, SP-A, TDO2, AhR, and NQO1. Like SP-A, cAMP induction of NRF2 was prevented when cells were exposed to hypoxia. NRF2 knockdown inhibited induction of C/EBPß, PPARγ, and immune modulators. Binding of endogenous NRF2 to promoters of SP-A and other immune modulator genes increased during HFL cell differentiation. In mouse fetal lung (MFL), a developmental increase in Nrf2, SP-A, Tdo2, Ahr, and Nqo1 and decrease in Keap1 occurred from 14.5 to 18.5 dpc. Developmental induction of Nrf2 in MFL was associated with increased nuclear localization of NF-κB p65, a decline in p38 MAPK phosphorylation, increase in the MAPK phosphatase, DUSP1, induction of the histone acetylase, CBP, and decline in the histone deacetylase, HDAC4. Thus, together with surfactant production, type II cells protect the alveolar epithelium through increased expression of NRF2 and immune modulators to prevent inflammation and oxidative stress. Our findings further suggest that lung cancer cells have usurped this developmental pathway to promote immune tolerance and enhance survival.


Asunto(s)
Regulación del Desarrollo de la Expresión Génica/inmunología , Pulmón , Factor 2 Relacionado con NF-E2 , Animales , Femenino , Humanos , Pulmón/embriología , Pulmón/inmunología , Ratones , Ratones Endogámicos ICR , Factor 2 Relacionado con NF-E2/biosíntesis , Factor 2 Relacionado con NF-E2/inmunología
3.
Nat Immunol ; 22(6): 699-710, 2021 06.
Artículo en Inglés | MEDLINE | ID: mdl-34040226

RESUMEN

It is increasingly recognized that immune development within mucosal tissues is under the control of environmental factors during early life. However, the cellular mechanisms that underlie such temporally and regionally restrictive governance of these processes are unclear. Here, we uncover an extrathymic pathway of immune development within the colon that is controlled by embryonic but not bone marrow-derived macrophages, which determines the ability of these organs to receive invariant natural killer T (iNKT) cells and allow them to establish local residency. Consequently, early-life perturbations of fetal-derived macrophages result in persistent decreases of mucosal iNKT cells and is associated with later-life susceptibility or resistance to iNKT cell-associated mucosal disorders. These studies uncover a host developmental program orchestrated by ontogenically distinct macrophages that is regulated by microbiota, and they reveal an important postnatal function of macrophages that emerge in fetal life.


Asunto(s)
Colitis/inmunología , Mucosa Intestinal/inmunología , Listeriosis/inmunología , Macrófagos/inmunología , Células T Invariantes Asociadas a Mucosa/inmunología , Animales , Proliferación Celular/genética , Colitis/microbiología , Colitis/patología , Colon/citología , Colon/embriología , Colon/inmunología , Colon/patología , Citocinas/metabolismo , Toxina Diftérica/administración & dosificación , Toxina Diftérica/inmunología , Modelos Animales de Enfermedad , Embrión de Mamíferos , Femenino , Microbioma Gastrointestinal/inmunología , Regulación del Desarrollo de la Expresión Génica/inmunología , Vida Libre de Gérmenes , Humanos , Mucosa Intestinal/citología , Mucosa Intestinal/embriología , Mucosa Intestinal/patología , Listeriosis/microbiología , Listeriosis/patología , Macrófagos/metabolismo , Masculino , Proteínas de la Membrana/genética , Ratones , Ratones Noqueados , RNA-Seq , Transducción de Señal/genética , Transducción de Señal/inmunología
4.
Mol Immunol ; 132: 53-59, 2021 04.
Artículo en Inglés | MEDLINE | ID: mdl-33545625

RESUMEN

Neospora caninum is a leading cause of abortion in cattle worldwide. The study of the immune response against N. caninum is critical to understand its epidemiology, pathogenesis, diagnosis and, ultimately, in preventing and controlling bovine neosporosis. Herein, we determined the gene expression of innate immune components endosomal RNA-sensing TLRs, BMAP28 cathelicidin, TNF-α and IL-10 and characterized the variation in both IgG ratio and avidity at delivery in N. caninum-infected heifers challenged at day 210 of gestation, colostrum and their calves. Increased BMAP28 expression was observed not only in colostrum but also in peripheral blood mononuclear cells (PBMC) and umbilical cord of calves from N. caninum-infected heifers in comparison with mock-infected control group. In addition, statistically significant decrease of TLR7 and IL-10 expression levels were observed in umbilical cord, suggesting an attempt to avoid an exacerbated immune response against the parasite. At delivery, serum and colostrum samples from infected group evidenced specific IgG anti-N. caninum. Infected heifers showed IgG1/IgG2 ratios <1 and high avidity specific IgG. As expected, colostrum samples of these animals exhibited a high IgG1 concentration and elevated avidity values. Three out of four calves from N. caninum-infected heifers had specific IgG with IgG1/IgG2 ratios>1 and lower avidity values before colostrum intake. Interestingly, both IgG1/IgG2 ratios and avidity values increased in seropositive calves after colostrum intake. Overall, this study provides novel information on neonatal immunity in congenitally infected calves, which is essential to understand how the immune pathways could be manipulated or immune components could be employed in order to improve protection against neosporosis.


Asunto(s)
Bovinos/inmunología , Calostro/inmunología , Regulación del Desarrollo de la Expresión Génica/inmunología , Inmunidad Humoral , Inmunidad Innata , Neospora/inmunología , Receptores Toll-Like/metabolismo , Animales , Anticuerpos Antiprotozoarios/inmunología , Bovinos/embriología , Bovinos/metabolismo , Bovinos/parasitología , Enfermedades de los Bovinos/genética , Enfermedades de los Bovinos/inmunología , Enfermedades de los Bovinos/metabolismo , Enfermedades de los Bovinos/parasitología , Femenino , Inmunoglobulina G/inmunología , Interleucina-10/genética , Interleucina-10/metabolismo , Leucocitos Mononucleares/inmunología , Leucocitos Mononucleares/metabolismo , Embarazo , Proteínas/genética , Proteínas/metabolismo , Receptor Toll-Like 7/genética , Receptor Toll-Like 7/metabolismo , Receptores Toll-Like/genética , Factor de Necrosis Tumoral alfa/genética , Factor de Necrosis Tumoral alfa/metabolismo , Cordón Umbilical/metabolismo
5.
Proc Natl Acad Sci U S A ; 118(9)2021 03 02.
Artículo en Inglés | MEDLINE | ID: mdl-33622787

RESUMEN

HLA-C arose during evolution of pregnancy in the great apes 10 to 15 million years ago. It has a dual function on placental extravillous trophoblasts (EVTs) as it contributes to both tolerance and immunity at the maternal-fetal interface. The mode of its regulation is of considerable interest in connection with the biology of pregnancy and pregnancy abnormalities. First-trimester primary EVTs in which HLA-C is highly expressed, as well as JEG3, an EVT model cell line, were employed. Single-cell RNA-seq data and quantitative PCR identified high expression of the transcription factor ELF3 in those cells. Chromatin immunoprecipitation (ChIP)-PCR confirmed that both ELF3 and MED1 bound to the proximal HLA-C promoter region. However, binding of RFX5 to this region was absent or severely reduced, and the adjacent HLA-B locus remained closed. Expression of HLA-C was inhibited by ELF3 small interfering RNAs (siRNAs) and by wrenchnolol treatment. Wrenchnolol is a cell-permeable synthetic organic molecule that mimics ELF3 and is relatively specific for binding to ELF3's coactivator, MED23, as our data also showed in JEG3. Moreover, the ELF3 gene is regulated by a superenhancer that spans more than 5 Mb, identified by assay for transposase-accessible chromatin using sequencing (ATAC-seq), as well as by its sensitivity to (+)-JQ1 (inhibitor of BRD4). ELF3 bound to its own promoter, thus creating an autoregulatory feedback loop that establishes expression of ELF3 and HLA-C in trophoblasts. Wrenchnolol blocked binding of MED23 to ELF3, thus disrupting the positive-feedback loop that drives ELF3 expression, with down-regulation of HLA-C expression as a consequence.


Asunto(s)
Proteínas de Unión al ADN/genética , Elementos de Facilitación Genéticos , Retroalimentación Fisiológica , Antígenos HLA-C/genética , Proteínas Proto-Oncogénicas c-ets/genética , Factores de Transcripción/genética , Trofoblastos/inmunología , Aborto Legal , Adamantano/farmacología , Azepinas/farmacología , Línea Celular , Proteínas de Unión al ADN/antagonistas & inhibidores , Proteínas de Unión al ADN/inmunología , Femenino , Regulación del Desarrollo de la Expresión Génica/inmunología , Antígenos HLA-B/genética , Antígenos HLA-B/inmunología , Antígenos HLA-C/inmunología , Humanos , Inmunidad Materno-Adquirida , Indoles/farmacología , Complejo Mediador/genética , Complejo Mediador/inmunología , Subunidad 1 del Complejo Mediador/genética , Subunidad 1 del Complejo Mediador/inmunología , Embarazo , Primer Trimestre del Embarazo , Cultivo Primario de Células , Regiones Promotoras Genéticas , Unión Proteica , Proteínas Proto-Oncogénicas c-ets/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-ets/inmunología , ARN Interferente Pequeño/genética , ARN Interferente Pequeño/inmunología , Factores de Transcripción del Factor Regulador X/genética , Factores de Transcripción del Factor Regulador X/inmunología , Transducción de Señal , Factores de Transcripción/antagonistas & inhibidores , Factores de Transcripción/inmunología , Triazoles/farmacología , Trofoblastos/citología , Trofoblastos/efectos de los fármacos
6.
Genes (Basel) ; 12(1)2021 01 19.
Artículo en Inglés | MEDLINE | ID: mdl-33477746

RESUMEN

Published studies show that most of the human cancer xenograft studies in zebrafish embryos have used incubation temperatures in the range of 32-34 °C for 3-6 days post-injection, trying to find a compromise temperature between the zebrafish embryos (28 °C) and the human injected cells (37 °C). While this experimental setup is widely used, a question remains: is possible to overcome the drawbacks caused by a suboptimal temperature for the injected cells? To clarify the effect of temperature and injected cells on the host, in this study, we analyzed the development and health of the last in response to different temperatures in the presence or absence of injected human cancer cells. Comparing different incubation temperatures (28, 34 and 36 °C), we determined morphological abnormalities and developmental effects in injected and non-injected embryos at different time points. Besides this, the expression of selected genes was determined by qPCR to determine temperature affected metabolic processes in the embryos. The results indicate that an incubation temperature of 36 °C during a period of 48 h is suitable for xenotransplantation without morphological or metabolic changes that could be affecting the host or the injected cells, allowing them to proliferate near their optimal temperature.


Asunto(s)
Regulación del Desarrollo de la Expresión Génica/inmunología , Calor/efectos adversos , Neoplasias/inmunología , Ensayos Antitumor por Modelo de Xenoinjerto/métodos , Pez Cebra/fisiología , Animales , Línea Celular Tumoral/fisiología , Línea Celular Tumoral/trasplante , Proliferación Celular/genética , Embrión no Mamífero/fisiología , Humanos , Inmunidad Innata/genética , Neoplasias/patología , Especificidad de la Especie
7.
Nat Commun ; 12(1): 464, 2021 01 19.
Artículo en Inglés | MEDLINE | ID: mdl-33469015

RESUMEN

Conventional dendritic cells (cDC) are key activators of naive T cells, and can be targeted in adults to induce adaptive immunity, but in early life are considered under-developed or functionally immature. Here we show that, in early life, when the immune system develops, cDC2 exhibit a dual hematopoietic origin and, like other myeloid and lymphoid cells, develop in waves. Developmentally distinct cDC2 in early life, despite being distinguishable by fate mapping, are transcriptionally and functionally similar. cDC2 in early and adult life, however, are exposed to distinct cytokine environments that shape their transcriptional profile and alter their ability to sense pathogens, secrete cytokines and polarize T cells. We further show that cDC2 in early life, despite being distinct from cDC2 in adult life, are functionally competent and can induce T cell responses. Our results thus highlight the potential of harnessing cDC2 for boosting immunity in early life.


Asunto(s)
Inmunidad Adaptativa/fisiología , Diferenciación Celular/genética , Citocinas/metabolismo , Células Dendríticas/inmunología , Regulación del Desarrollo de la Expresión Génica/inmunología , Factores de Edad , Animales , Diferenciación Celular/inmunología , Separación Celular , Células Dendríticas/metabolismo , Femenino , Citometría de Flujo , Células Madre Hematopoyéticas/fisiología , Masculino , Ratones , Ratones Transgénicos , Modelos Animales , Cultivo Primario de Células , RNA-Seq , Análisis de la Célula Individual , Linfocitos T/inmunología , Transcriptoma/inmunología
8.
FEBS J ; 288(5): 1533-1545, 2021 03.
Artículo en Inglés | MEDLINE | ID: mdl-32705746

RESUMEN

MicroRNAs (miRNAs) post-transcriptionally repress almost all genes in mammals and thereby form an additional layer of gene regulation. As such, miRNAs impact on nearly every physiological process and have also been associated with cancer. Prominent examples of such miRNAs can be found in the miR-15 family, composed of the bicistronic clusters miR-15a/16-1, miR-15b/16-2, and miR-497/195. In particular, the miR-15a/16-1 cluster is deleted in almost two thirds of all chronic B lymphocytic leukemia (CLL) cases, a phenotype that is also recapitulated by miR-15a/16-1-deficient as well as miR-15b/16-2-deficient mice. Under physiological conditions, those two clusters have been implicated in T-cell function, and B-cell and natural killer (NK) cell development; however, it is unclear whether miR-497 and miR-195 confer similar roles in health and disease. Here, we have generated a conditional mouse model for tissue-specific deletion of miR-497 and miR-195. While mice lacking miR-15a/16-1 in the hematopoietic compartment developed clear signs of CLL over time, aging mice deficient for miR-497/195 did not show such a phenotype. Likewise, loss of miR-15a/16-1 impaired NK and early B-cell development, whereas miR-497/195 was dispensable for these processes. In fact, a detailed analysis of miR-497/195-deficient mice did not reveal any effect on steady-state hematopoiesis or immune cell function. Unexpectedly, even whole-body deletion of the cluster was well-tolerated and had no obvious impact on embryonic development or healthy life span. Therefore, we postulate that the miR-497/195 cluster is redundant to its paralog clusters or that its functional relevance is restricted to certain physiological and pathological conditions.


Asunto(s)
Regulación del Desarrollo de la Expresión Génica/inmunología , Leucemia Linfocítica Crónica de Células B/genética , MicroARNs/genética , Animales , Animales Modificados Genéticamente , Linfocitos B/inmunología , Linfocitos B/patología , Médula Ósea/inmunología , Médula Ósea/patología , Proliferación Celular , Modelos Animales de Enfermedad , Femenino , Edición Génica/métodos , Homeostasis/genética , Homeostasis/inmunología , Humanos , Inmunofenotipificación , Células Asesinas Naturales/inmunología , Células Asesinas Naturales/patología , Leucemia Linfocítica Crónica de Células B/inmunología , Leucemia Linfocítica Crónica de Células B/metabolismo , Leucemia Linfocítica Crónica de Células B/patología , Ganglios Linfáticos/inmunología , Ganglios Linfáticos/patología , Masculino , Ratones , MicroARNs/inmunología , Células Madre Embrionarias de Ratones/inmunología , Células Madre Embrionarias de Ratones/patología , Eliminación de Secuencia , Transducción de Señal , Análisis de la Célula Individual/métodos , Bazo/inmunología , Bazo/patología , Linfocitos T/inmunología , Linfocitos T/patología
9.
J Reprod Immunol ; 142: 103210, 2020 11.
Artículo en Inglés | MEDLINE | ID: mdl-33011635

RESUMEN

BACKGROUD: Prostaglandin E2 (PGE2), an inflammatory mediator, modulates cytokines, regulates immune responses in reproductive processes and stimulates inflammatory reactions via the prostaglandin E2 receptor 2 (EP2). However, the regulatory effects of EP2 signaling on trophoblasts and its role in unexplained recurrent miscarriage (uRM) remains unclear. PATIENTS AND METHODS: A total of 19 placentas from patients with a history of more than two consecutive pregnancy losses of unknown cause (uRM group) and placentas of 19 healthy patients following a legal termination of their pregnancy were used for PGE2 receptor (EP1, EP2 and EP4) expression analyses via immunohistochemistry. Double immunofluorescence was also used to identify EP2 expressing cells in the decidua. Finally, HTR-8/SVneo cells were used to clarify the role of EP2 in in vitro experiments. RESULTS: The expression of EP2 and EP4 was found to be reduced in the syncytiotrophoblast and decidua of uRM patients. A selective EP2 receptor antagonist (PF-04,418,948) reduced the proliferation and secretion of ß-hCG, inhibited interleukin -6 (IL-6) and interleukin-8 (IL-8) and up-regulated the production of the tumor necrosis factor-α (TNF-α) and plasminogen activator inhibitor type 1 (PAI-1) in HTR-8/SVneo cells in vitro. CONCLUSION: PGE2-EP2 signaling pathway may represent a novel therapy option for uRM. The involvement of EP2 in uRM acts perhaps via inflammatory cytokines and indicates that the PGE2-EP2 signaling pathway might represent an unexplored etiology for uRM.


Asunto(s)
Aborto Habitual/inmunología , Citocinas/metabolismo , Dinoprostona/metabolismo , Subtipo EP2 de Receptores de Prostaglandina E/genética , Adulto , Línea Celular , Proliferación Celular/efectos de los fármacos , Decidua/inmunología , Decidua/metabolismo , Regulación hacia Abajo/inmunología , Femenino , Regulación del Desarrollo de la Expresión Génica/efectos de los fármacos , Regulación del Desarrollo de la Expresión Génica/inmunología , Humanos , Inmunohistoquímica , Persona de Mediana Edad , Embarazo , Subtipo EP2 de Receptores de Prostaglandina E/análisis , Subtipo EP2 de Receptores de Prostaglandina E/antagonistas & inhibidores , Subtipo EP2 de Receptores de Prostaglandina E/metabolismo , Subtipo EP4 de Receptores de Prostaglandina E/análisis , Subtipo EP4 de Receptores de Prostaglandina E/genética , Subtipo EP4 de Receptores de Prostaglandina E/metabolismo , Transducción de Señal/efectos de los fármacos , Transducción de Señal/genética , Transducción de Señal/inmunología , Trofoblastos/efectos de los fármacos , Trofoblastos/inmunología , Trofoblastos/metabolismo
10.
Int J Mol Sci ; 21(19)2020 Sep 28.
Artículo en Inglés | MEDLINE | ID: mdl-32998388

RESUMEN

Aging is the most relevant risk factor for cardiovascular diseases which are the main cause of mortality in industrialized countries. In this context, there is a progressive loss of cardiovascular homeostasis that translates in illness and death. The study of long living individuals (LLIs), which show compression of morbidity toward the end of their life, is a valuable approach to find the key to delay aging and postpone associate cardiovascular events. A contribution to the age-related decline of cardiovascular system (CVS) comes from the immune system; indeed, it is dysfunctional during aging, a process described as immunosenescence and comprises the combination of several processes overpowering both innate and adaptative immune system. We have recently discovered a longevity-associated variant (LAV) in bactericidal/permeability-increasing fold-containing family B member 4 (BPIFB4), which is a secreted protein able to enhance endothelial function through endothelial nitric oxide synthase (eNOS) activation and capable to protect from hypertension, atherosclerosis, diabetic cardiopathy, frailty, and inflammaging. Here, we sum up the state of the art of the mechanisms involved in the main pathological processes related to CVD (atherosclerosis, aging, diabetic cardiopathy, and frailty) and shed light on the therapeutic effects of LAV-BPIFB4 in these contexts.


Asunto(s)
Aterosclerosis/genética , Cardiomiopatías Diabéticas/genética , Fragilidad/genética , Hipertensión/genética , Inmunosenescencia/genética , Longevidad/genética , Fosfoproteínas/genética , Inmunidad Adaptativa , Factores de Edad , Animales , Aterosclerosis/inmunología , Aterosclerosis/prevención & control , Cardiomiopatías Diabéticas/inmunología , Cardiomiopatías Diabéticas/prevención & control , Fragilidad/inmunología , Fragilidad/prevención & control , Regulación del Desarrollo de la Expresión Génica/inmunología , Terapia Genética/métodos , Humanos , Hipertensión/inmunología , Hipertensión/prevención & control , Inmunidad Innata , Péptidos y Proteínas de Señalización Intercelular , Longevidad/inmunología , Ratones , Óxido Nítrico Sintasa de Tipo III/genética , Óxido Nítrico Sintasa de Tipo III/inmunología , Fosfoproteínas/inmunología , Isoformas de Proteínas/genética , Isoformas de Proteínas/inmunología , Factores de Riesgo
11.
PLoS One ; 15(9): e0228974, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32976488

RESUMEN

Parental care elevates reproductive success by allocating resources into the upbringing of the offspring. However, it also imposes strong costs for the care-giving parent and can foster sexual dimorphism. Trade-offs between the reproductive system and the immune system may result in differential immunological capacities between the care-providing and the non-care-providing parent. Usually, providing care is restricted to the female sex making it impossible to study a sex-independent influence of parental investment on sexual immune dimorphism. The decoupling of sex-dependent parental investment and their influences on the parental immunological capacity, however, is possible in syngnathids, which evolved the unique male pregnancy on a gradient ranging from a simple carrying of eggs on the trunk (Nerophinae, low paternal investment) to full internal pregnancy (Syngnathus, high paternal investment). In this study, we compared candidate gene expression between females and males of different gravity stages in three species of syngnathids (Syngnathus typhle, Syngnathus rostellatus and Nerophis ophidion) with different male pregnancy intensities to determine how parental investment influences sexual immune dimorphism. While our data failed to detect sexual immune dimorphism in the subset of candidate genes assessed, we show a parental care specific resource-allocation trade-off between investment into pregnancy and immune defense when parental care is provided.


Asunto(s)
Peces/fisiología , Regulación del Desarrollo de la Expresión Génica/inmunología , Sistema Inmunológico/fisiología , Caracteres Sexuales , Procesos de Determinación del Sexo/inmunología , Animales , Femenino , Perfilación de la Expresión Génica , Masculino , Responsabilidad Parental , Procesos de Determinación del Sexo/genética
12.
J Reprod Immunol ; 142: 103188, 2020 11.
Artículo en Inglés | MEDLINE | ID: mdl-32846354

RESUMEN

Effective bidirectional communication between the embryo and dam improves the reproductive efficiency of dairy cows. Possible role of immunosuppressive indolamine-2, 3-dioxygenase 1 (IDO1) enzyme in the regulation of maternal systemic cytokine balance/shift during early pregnancy establishment along with various interferon-stimulated genes (ISGs) expression in neutrophils and peripheral blood mononuclear cell (PBMCs) were investigated in crossbred cows. Blood was collected on days 0 i.e. day of Artificial Insemination (AI), 10, 18 and 36 post-AI followed by isolation of neutrophils and PBMCs for gene expression study of IDO1, anti-inflammatory cytokines (IL-4, IL-10 and TGFß1), pro-inflammatory cytokines (IFNγ and TNFα) and ISGs (ISG15, MX1, MX2, OAS1) in pregnant and non-pregnant cows. Cows were grouped as pregnant and non-pregnant after pregnancy confirmation by non-return to heat, ultrasonography, per rectal examination along with progesterone and IFNτ assay. Significantly (P < 0.05) higher relative mRNA expression of IDO1 and anti-inflammatory cytokines on days 10 and 18 post-AI were observed in both neutrophils and PBMCs of pregnant cows. Pregnant cows showed significantly (P < 0.05) higher mRNA transcripts of IFNγ and TNFα genes on days 18 post-AI in both neutrophils and PBMCs. Expression of ISGs was higher (P < 0.05) on day 10th and 18th post AI in both the neutrophils and PBMCs of pregnant cows. The study indicates that systemic immune regulation by IDO1 (through cytokine shift) and ISGs in peripheral immune cells are essential for the establishment of pregnancy and may be targeted in future as biomarkers for pregnancy diagnosis.


Asunto(s)
Implantación del Embrión/inmunología , Indolamina-Pirrol 2,3,-Dioxigenasa/metabolismo , Interferón gamma/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Animales , Bovinos , Cuerpo Lúteo/inmunología , Cuerpo Lúteo/metabolismo , Embrión de Mamíferos/inmunología , Femenino , Perfilación de la Expresión Génica , Regulación del Desarrollo de la Expresión Génica/inmunología , Leucocitos Mononucleares/inmunología , Leucocitos Mononucleares/metabolismo , Neutrófilos/inmunología , Neutrófilos/metabolismo , Embarazo , Balance Th1 - Th2
13.
J Cell Biol ; 219(10)2020 10 05.
Artículo en Inglés | MEDLINE | ID: mdl-32756905

RESUMEN

Notch signaling is the dominant intercellular signaling input during the earliest stages of T cell development in the thymus. Although Notch1 is known to be indispensable, we show that it does not mediate all Notch signaling in precommitment stages: Notch2 initially works in parallel to promote early murine T cell development and antagonize other fates. Notch-regulated target genes before and after T lineage commitment change dynamically, and we show that this partially reflects shifts in genome-wide DNA binding by RBPJ, the transcription factor activated by complex formation with the Notch intracellular domain. Although Notch signaling and transcription factor PU.1 can activate some common targets in precommitment T progenitors, Notch signaling and PU.1 activity have functionally antagonistic effects on multiple targets, delineating separation of pro-T cells from alternative PU.1-dependent fates. These results define a distinct mechanism of Notch signal response that distinguishes the initial stages of murine T cell development.


Asunto(s)
Proteínas Proto-Oncogénicas/genética , Receptor Notch1/genética , Receptor Notch2/genética , Linfocitos T/metabolismo , Transactivadores/genética , Animales , Diferenciación Celular , Regulación del Desarrollo de la Expresión Génica/inmunología , Humanos , Ratones , Transducción de Señal/genética , Linfocitos T/inmunología
14.
Nat Commun ; 11(1): 3761, 2020 07 28.
Artículo en Inglés | MEDLINE | ID: mdl-32724101

RESUMEN

Chronic immune-mediated diseases of adulthood often originate in early childhood. To investigate genetic associations between neonatal immunity and disease, we map expression quantitative trait loci (eQTLs) in resting myeloid cells and CD4+ T cells from cord blood samples, as well as in response to lipopolysaccharide (LPS) or phytohemagglutinin (PHA) stimulation, respectively. Cis-eQTLs are largely specific to cell type or stimulation, and 31% and 52% of genes with cis-eQTLs have response eQTLs (reQTLs) in myeloid cells and T cells, respectively. We identified cis regulatory factors acting as mediators of trans effects. There is extensive colocalisation between condition-specific neonatal cis-eQTLs and variants associated with immune-mediated diseases, in particular CTSH had widespread colocalisation across diseases. Mendelian randomisation shows causal neonatal gene expression effects on disease risk for BTN3A2, HLA-C and others. Our study elucidates the genetics of gene expression in neonatal immune cells, and aetiological origins of autoimmune and allergic diseases.


Asunto(s)
Enfermedades Autoinmunes/genética , Desarrollo Infantil/fisiología , Regulación del Desarrollo de la Expresión Génica/inmunología , Hipersensibilidad/genética , Sitios de Carácter Cuantitativo/inmunología , Enfermedades Autoinmunes/inmunología , Butirofilinas/genética , Butirofilinas/metabolismo , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/metabolismo , Catepsina H/genética , Catepsina H/metabolismo , Niño , Preescolar , Conjuntos de Datos como Asunto , Sangre Fetal/citología , Perfilación de la Expresión Génica , Redes Reguladoras de Genes/inmunología , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Antígenos HLA-C/genética , Antígenos HLA-C/metabolismo , Humanos , Hipersensibilidad/inmunología , Lactante , Recién Nacido , Análisis de la Aleatorización Mendeliana , Células Mieloides/inmunología , Células Mieloides/metabolismo , Análisis de Secuencia por Matrices de Oligonucleótidos , Polimorfismo de Nucleótido Simple , Estudios Prospectivos
15.
Theranostics ; 10(18): 8018-8035, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32724455

RESUMEN

Unlike adult cardiomyocytes, neonatal cardiomyocytes can readily proliferate that contributes to a transient regenerative potential after myocardial injury in mice. We have recently reported that CD4+ regulatory T-cells promote this process; however, the role of other CD4+ T-cell subsets as well as CD8+ T-cells in postnatal heart regeneration has been less studied. Methods: by comparing the regenerating postnatal day (P) 3 and the non-regenerating P8 heart after injury, we revealed the heterogeneity of CD4+ and CD8+ T-cells in the myocardium through single cell analysis. We also specifically ablated CD4+ and CD8+ T-cells using the lytic anti-CD4 and -CD8 monoclonal antibodies, respectively, in juvenile mice at P8 after myocardial injury. Results: we observe significantly more CD4+FOXP3- conventional T-cells in the P8 heart when compared to that of the P3 heart within a week after injury. Surprisingly, such a difference is not seen in CD8+ T-cells that appear to have no function as their depletion does not reactivate heart regeneration. On the other hand, specific ablation of CD4+ T-cells contributes to mitigated cardiac fibrosis and increased cardiomyocyte proliferation after injury in juvenile mice. Single-cell transcriptomic profiling reveals a pro-fibrotic CD4+ T-cell subset in the P8 but not P3 heart. Moreover, there are likely more Th1 and Th17 cells in the P8 than P3 heart. We further demonstrate that cytokines of Th1 and Th17 cells can directly reduce the proliferation and increase the apoptosis of neonatal cardiomyocytes. Moreover, ablation of CD4+ T-cells can directly or indirectly facilitate the polarization of macrophages away from the pro-fibrotic M2-like signature in the juvenile heart. Nevertheless, ablation of CD4+ T-cells alone does not offer the same protection in the adult heart after myocardial infarction, suggesting a developmental change of immune cells including CD4+ T-cells in the regulation of age-related mammalian heart repair. Conclusions: our results demonstrate that ablation of CD4+ but not CD8+ T-cells promotes heart regeneration in juvenile mice; and CD4+ T-cells play a distinct role in the regulation of heart regeneration and repair during development.


Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Infarto del Miocardio/inmunología , Daño por Reperfusión Miocárdica/inmunología , Regeneración/inmunología , Subgrupos de Linfocitos T/inmunología , Envejecimiento/fisiología , Animales , Animales Recién Nacidos , Anticuerpos Monoclonales/administración & dosificación , Antígenos CD4/antagonistas & inhibidores , Antígenos CD8/antagonistas & inhibidores , Linfocitos T CD8-positivos/efectos de los fármacos , Linfocitos T CD8-positivos/inmunología , Células Cultivadas , Modelos Animales de Enfermedad , Femenino , Regulación del Desarrollo de la Expresión Génica/inmunología , Corazón/crecimiento & desarrollo , Humanos , Masculino , Ratones , Infarto del Miocardio/tratamiento farmacológico , Infarto del Miocardio/patología , Daño por Reperfusión Miocárdica/patología , Daño por Reperfusión Miocárdica/prevención & control , Miocardio/citología , Miocardio/inmunología , Miocardio/patología , Miocitos Cardíacos/fisiología , Cultivo Primario de Células , RNA-Seq , Regeneración/efectos de los fármacos , Análisis de la Célula Individual , Subgrupos de Linfocitos T/efectos de los fármacos
16.
Proc Natl Acad Sci U S A ; 117(27): 15772-15777, 2020 07 07.
Artículo en Inglés | MEDLINE | ID: mdl-32581122

RESUMEN

During pregnancy, invading HLA-G+ extravillous trophoblasts (EVT) play a key role in placental development, uterine spiral artery remodeling, and prevention of detrimental maternal immune responses to placental and fetal antigens. Failures of these processes are suggested to play a role in the development of pregnancy complications, but very little is known about the underlying mechanisms. Here we present validated methods to purify and culture primary HLA-G+ EVT from the placental disk and chorionic membrane from healthy term pregnancy. Characterization of HLA-G+ EVT from term pregnancy compared to first trimester revealed their unique phenotypes, gene expression profiles, and differing capacities to increase regulatory T cells (Treg) during coculture assays, features that cannot be captured by using surrogate cell lines or animal models. Furthermore, clinical variables including gestational age and fetal sex significantly influenced EVT biology and function. These methods and approaches form a solid basis for further investigation of the role of HLA-G+ EVT in the development of detrimental placental inflammatory responses associated with pregnancy complications, including spontaneous preterm delivery and preeclampsia.


Asunto(s)
Antígenos HLA-G/inmunología , Inmunidad Innata/genética , Placentación/inmunología , Preeclampsia/inmunología , Línea Celular , Movimiento Celular/inmunología , Femenino , Regulación del Desarrollo de la Expresión Génica/inmunología , Humanos , Relaciones Materno-Fetales , Placenta/inmunología , Placenta/metabolismo , Preeclampsia/patología , Embarazo , Primer Trimestre del Embarazo , Trofoblastos/inmunología
17.
Proc Natl Acad Sci U S A ; 117(25): 14342-14353, 2020 06 23.
Artículo en Inglés | MEDLINE | ID: mdl-32513716

RESUMEN

Immature T cells undergo a process of positive selection in the thymus when their new T cell receptor (TCR) engages and signals in response to self-peptides. As the T cell matures, a slew of negative regulatory molecules, including the inhibitory surface glycoprotein CD5, are up-regulated in proportion to the strength of the self-peptide signal. Together these regulators dampen TCR-proximal signaling and help avoid any subsequent peripheral activation of T cells by self-peptides. Paradoxically, antigen-specific T cells initially expressing more CD5 (CD5hi) have been found to better persist as effector/memory cells after a peripheral challenge. The molecular mechanisms underlying such a duality in CD5 function is not clear. We found that CD5 alters the basal activity of the NF-κB signaling in resting peripheral T cells. When CD5 was conditionally ablated, T cells were unable to maintain higher expression of the cytoplasmic NF-κB inhibitor IκBα. Consistent with this, resting CD5hi T cells expressed more of the NF-κB p65 protein than CD5lo cells, without significant increases in transcript levels, in the absence of TCR signals. This posttranslationally stabilized cellular NF-κB depot potentially confers a survival advantage to CD5hi T cells over CD5lo ones. Taken together, these data suggest a two-step model whereby the strength of self-peptide-induced TCR signal lead to the up-regulation of CD5, which subsequently maintains a proportional reserve of NF-κB in peripheral T cells poised for responding to agonistic antigen-driven T cell activation.


Asunto(s)
Antígenos CD5/metabolismo , Regulación del Desarrollo de la Expresión Génica/inmunología , Inhibidor NF-kappaB alfa/metabolismo , Proteína Tirosina Fosfatasa no Receptora Tipo 6/metabolismo , Linfocitos T/inmunología , Traslado Adoptivo , Animales , Presentación de Antígeno/inmunología , Antígenos CD5/genética , Línea Celular Tumoral , Separación Celular , Supervivencia Celular/inmunología , Femenino , Citometría de Flujo , Lipopolisacáridos/inmunología , Activación de Linfocitos , Ratones , Ratones Noqueados , Modelos Animales , Cultivo Primario de Células , Receptores de Antígenos de Linfocitos T alfa-beta/genética , Receptores de Antígenos de Linfocitos T alfa-beta/metabolismo , Transducción de Señal/inmunología , Linfocitos T/metabolismo , Linfocitos T/trasplante , Timo/citología , Timo/crecimiento & desarrollo , Timo/inmunología , Factor de Transcripción ReIA/metabolismo , Regulación hacia Arriba
18.
Fish Shellfish Immunol ; 99: 239-242, 2020 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-32058099

RESUMEN

The co-receptor CD4 plays an important role in distinguishing between helper T-cell (Th) and cytotoxic T lymphocyte (CTL). In the present study, we investigated the molecular features of CD4-2 cDNA to facilitate understanding of their roles in cobia (Rachycentron canadum). Two CD4-2 molecules have been identified and exhibited 16.10% amino acids identity with each other. The cDNA of CD4-2A consists of a 993 bp ORF encoding 330 aa with long intracytoplasmic tail containing conserved protein tyrosine kinase p56Lck binding (C-X-C) motif, a transmembrane region, and two extracellular Ig-like (Ig-like) domains are predicted. Comparatively, the cDNA of cobia CD4-2B consists of a 990 bp ORF encoding 329 aa without a transmembrane domain as well as C-X-C motif, and three Ig-like domains are present. Homology comparison showed that the CD4-2A aa sequence of cobia showed high similarity and similar structural features to CD4-2 from other species, while the deduced CD4-2B protein shares higher structural similarity to CD4-1 group. Phylogenetic analysis indicated that cobia CD4-2A was closer with CD4-2 molecules in other fish species, distant from the clade formed by fish CD4-1 and mammalian CD4 sequences. However, cobia CD4-2B grouped with other known teleost CD4-1 sequences. The expression pattern of CD4-2A and CD4-2B mRNA during the embryonic development followed the trend of an initial increase after fertilized, providing evidence of maternal transfer of CD4-2 homologues to the developing cobia embryos and larvae. All of these results are useful for better understanding of cell-mediated immunity of cobia.


Asunto(s)
Antígenos CD4/metabolismo , Proteínas de Peces/metabolismo , Regulación del Desarrollo de la Expresión Génica/fisiología , Perciformes/metabolismo , Animales , Antígenos CD4/genética , Proteínas de Peces/genética , Regulación del Desarrollo de la Expresión Génica/inmunología , Perciformes/inmunología , ARN Mensajero/genética , ARN Mensajero/metabolismo
20.
Sci Adv ; 5(12): eaaw1715, 2019 12.
Artículo en Inglés | MEDLINE | ID: mdl-31844658

RESUMEN

Follicular helper T (TFH) cells are essential for generating protective humoral immunity. To date, microRNAs (miRNAs) have emerged as important players in regulating TFH cell biology. Here, we show that loss of miR-23~27~24 clusters in T cells resulted in elevated TFH cell frequencies upon different immune challenges, whereas overexpression of this miRNA family led to reduced TFH cell responses. Mechanistically, miR-23~27~24 clusters coordinately control TFH cells through targeting a network of genes that are crucial for TFH cell biology. Among them, thymocyte selection-associated HMG-box protein (TOX) was identified as a central transcription regulator in TFH cell development. TOX is highly up-regulated in both mouse and human TFH cells in a BCL6-dependent manner. In turn, TOX promotes the expression of multiple molecules that play critical roles in TFH cell differentiation and function. Collectively, our results establish a key miRNA regulon that maintains optimal TFH cell responses for resultant humoral immunity.


Asunto(s)
Diferenciación Celular/genética , Inmunidad Humoral/genética , Linfocitos T Colaboradores-Inductores/inmunología , Linfocitos T/inmunología , Animales , Regulación del Desarrollo de la Expresión Génica/inmunología , Proteínas del Grupo de Alta Movilidad/genética , Humanos , Inmunidad Humoral/inmunología , Activación de Linfocitos/inmunología , Ratones , MicroARNs/genética , Proteínas Proto-Oncogénicas c-bcl-6/genética , Transducción de Señal , Linfocitos T Colaboradores-Inductores/metabolismo
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