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1.
PLoS Genet ; 11(6): e1005251, 2015 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-26107960

RESUMEN

The lineage factor Foxp3 is essential for the development and maintenance of regulatory T cells, but little is known about the mechanisms involved. Here, we demonstrate that an N-terminal proline-rich interaction region is crucial for Foxp3's function. Subdomains within this key region link Foxp3 to several independent mechanisms of transcriptional regulation. Our study suggests that Foxp3, even in the absence of its DNA-binding forkhead domain, acts as a bridge between DNA-binding interaction partners and proteins with effector function permitting it to regulate a large number of genes. We show that, in one such mechanism, Foxp3 recruits class I histone deacetylases to the promoters of target genes, counteracting activation-induced histone acetylation and thereby suppressing their expression.


Asunto(s)
ADN/metabolismo , Factores de Transcripción Forkhead/metabolismo , Regulación de la Expresión Génica , Linfocitos T Reguladores/fisiología , Animales , Linaje de la Célula , Núcleo Celular/metabolismo , Femenino , Factores de Transcripción Forkhead/genética , Técnicas de Silenciamiento del Gen , Células HEK293 , Histona Desacetilasas/genética , Histona Desacetilasas/metabolismo , Histonas/metabolismo , Humanos , Interleucina-2/genética , Interleucina-2/metabolismo , Ratones Endogámicos BALB C , Regiones Promotoras Genéticas , Estructura Terciaria de Proteína , Linfocitos T Reguladores/citología
2.
Immunity ; 28(3): 402-13, 2008 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-18328743

RESUMEN

The interaction of T cells with dendritic cells (DCs) determines whether an immune response is launched or not. Recognition of antigen leads to formation of immunological synapses at the interface between the cells. The length of interaction is likely to determine the functional outcome, because it limits the number of MHC class II-peptide complexes that can be recruited into the synapse. Here, we show that regulatory T (Treg) cells and naive helper T (Th) cells interact differently with DCs in the absence of proinflammatory stimuli. Although differences in T cell receptor repertoire might contribute, Foxp3-induced phenotypic differences play a major role. We found that Neuropilin-1 (Nrp-1), which is expressed by most Treg cells but not naive Th cells, promoted prolonged interactions with immature DCs (iDCs), resulting in higher sensitivity to limiting amounts of antigen. This is likely to give Treg cells an advantage over naive Th cells, with the same specificity leading to a "default" suppression of immune responses in the absence of "danger signals."


Asunto(s)
Presentación de Antígeno/inmunología , Comunicación Celular/inmunología , Células Dendríticas/inmunología , Neuropilina-1/biosíntesis , Linfocitos T Reguladores/inmunología , Animales , Células Dendríticas/metabolismo , Citometría de Flujo , Antígenos de Histocompatibilidad Clase II , Inmunohistoquímica , Ratones , Receptores de Antígenos de Linfocitos T , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Linfocitos T Colaboradores-Inductores/inmunología , Linfocitos T Colaboradores-Inductores/metabolismo , Linfocitos T Reguladores/metabolismo , Transducción Genética
3.
Immunol Rev ; 241(1): 20-38, 2011 May.
Artículo en Inglés | MEDLINE | ID: mdl-21488887

RESUMEN

Antigen-presenting molecules vary between individuals of the same species, making it more difficult for pathogens to evade immune recognition and spread through the whole population. As a result of this genetic diversity, transplants between individuals are recognized as foreign and are rejected. This alloreactivity turns placental viviparity into a major immunological challenge. The maternal immune system has to balance the opposing needs of maintaining robust immune reactivity to protect both mother and fetus from invading pathogens, while at the same time tolerating highly immunogenic paternal alloantigens in order to sustain fetal integrity. Regulatory T cells are responsible for the establishment of tolerance by modulating the immune response, and uterine natural killer cells direct placentation by controlling trophoblast invasion. A variety of other cell types, including decidual stromal cells, dendritic cells, and immunomodulatory multipotent mesenchymal stromal cells, are found at the fetal-maternal interface. These cells conspire to establish a suitable environment for fetal development without compromising systemic immunity. Defects in any of these components can lead to gestational failure despite successful fertilization.


Asunto(s)
Tolerancia Inmunológica , Placentación/inmunología , Complicaciones del Embarazo/inmunología , Semen/inmunología , Linfocitos T Reguladores/inmunología , Animales , Femenino , Histocompatibilidad/inmunología , Humanos , Sistema Inmunológico , Inmunomodulación , Células Asesinas Naturales/inmunología , Intercambio Materno-Fetal , Embarazo/inmunología , Complicaciones del Embarazo/prevención & control
4.
J Immunol ; 189(8): 3947-56, 2012 Oct 15.
Artículo en Inglés | MEDLINE | ID: mdl-22988034

RESUMEN

CD4(+)Foxp3(+) regulatory T cells (Treg) are essential for immune homeostasis and maintenance of self-tolerance. They are produced in the thymus and also generated de novo in the periphery in a TGF-ß-dependent manner. Foxp3(+) Treg are also required to achieve tolerance to transplanted tissues when induced by coreceptor or costimulation blockade. Using TCR-transgenic mice to avoid issues of autoimmune pathology, we show that Foxp3 expression is both necessary and sufficient for tissue tolerance by coreceptor blockade. Moreover, the known need in tolerance induction for TGF-ß signaling to T cells can wholly be explained by its role in induction of Foxp3, as such signaling proved dispensable for the suppressive process. We analyzed the relative contribution of TGF-ß and Foxp3 to the transcriptome of TGF-ß-induced Treg and showed that TGF-ß elicited a large set of downregulated signature genes. The number of genes uniquely modulated due to the influence of Foxp3 alone was surprisingly limited. Retroviral-mediated conditional nuclear expression of Foxp3 proved sufficient to confer transplant-suppressive potency on CD4(+) T cells and was lost once nuclear Foxp3 expression was extinguished. These data support a dual role for TGF-ß and Foxp3 in induced tolerance, in which TGF-ß stimulates Foxp3 expression, for which sustained expression is then associated with acquisition of tolerance.


Asunto(s)
Factores de Transcripción Forkhead/biosíntesis , Factores de Transcripción Forkhead/genética , Linfocitos T Reguladores/inmunología , Tolerancia al Trasplante , Animales , Línea Celular Tumoral , Factores de Transcripción Forkhead/deficiencia , Supervivencia de Injerto/genética , Supervivencia de Injerto/inmunología , Humanos , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos CBA , Ratones Noqueados , Ratones Transgénicos , Transducción de Señal/genética , Transducción de Señal/inmunología , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismo , Linfocitos T Reguladores/metabolismo , Factor de Crecimiento Transformador beta/genética , Factor de Crecimiento Transformador beta/fisiología , Tolerancia al Trasplante/genética
5.
Eur J Immunol ; 42(6): 1436-48, 2012 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-22678900

RESUMEN

Regulatory T (Treg) cells are critically important for the maintenance of immunological tolerance. Both centrally arising natural nTreg cells and those emerging in the periphery in response to TGF-ß, iTreg cells, play a role in the control of unwanted immune responses. Treg cells adopt multiple mechanisms to inhibit effector T cells, yet it is unclear whether these mechanisms are shared by nTreg cells and iTreg cells alike. Here, we show that iTreg cells, like nTreg cells, are able to out-compete naïve T cells in clustering around dendritic cells (DCs). However, using both a tamoxifen-responsive inducible Foxp3 retroviral construct and TGF-ß-induced iTreg cells from hCD2-Foxp3 knock in reporter mice, we show that it is prior antigen-induced activation rather than Foxp3 expression per se that determines the ability of iTreg cells to competitively cluster around DCs. We found no difference in the capacity of iTreg cells to displace naïve T cells around DCs to that of Tr1, Th1, Th2, or Th9 cells. An important difference was, however, that clustering of iTreg cells around DCs, just as for naïve T cells, did not effectively activate DCs.


Asunto(s)
Células Dendríticas/inmunología , Factores de Transcripción Forkhead/análisis , Activación de Linfocitos , Linfocitos T Reguladores/inmunología , Factor de Crecimiento Transformador beta/farmacología , Secuencia de Aminoácidos , Animales , Agregación Celular , Polaridad Celular , Ratones , Ratones Endogámicos CBA , Datos de Secuencia Molecular , Linfocitos T Reguladores/efectos de los fármacos
7.
J Autoimmun ; 38(2-3): J103-8, 2012 May.
Artículo en Inglés | MEDLINE | ID: mdl-22004905

RESUMEN

Pregnancy frequently has a beneficial effect on the autoimmune disease Rheumatoid Arthritis, ranging from improvement in clinical symptoms to complete remission. Despite decades of study, a mechanistic explanation remains elusive. Here, we demonstrate that an analogous pregnancy-induced remission can be observed in a mouse model of arthritis. We demonstrate that during pregnancy mice are protected from collagen-induced arthritis, but are still capable of launching normal immune responses to influenza infections. We examine the role of regulatory T (T(R)) cells in this beneficial effect. T(R) cells are essential for many aspects of immune tolerance, including the suppression of autoimmune responses. Remarkably, transfer of regulatory T cells from pregnant 'protected' mice was sufficient to confer protection to non-pregnant mice. These results suggest that regulatory T cells are responsible for the pregnancy-induced amelioration of arthritis.


Asunto(s)
Artritis Experimental/inmunología , Enfermedades Autoinmunes/inmunología , Complicaciones del Embarazo/inmunología , Linfocitos T Reguladores/inmunología , Traslado Adoptivo , Animales , Artritis Experimental/prevención & control , Enfermedades Autoinmunes/prevención & control , Femenino , Humanos , Tolerancia Inmunológica , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Embarazo
8.
PLoS Biol ; 6(11): e276, 2008 Nov 11.
Artículo en Inglés | MEDLINE | ID: mdl-18998771

RESUMEN

Forkhead box p3 (Foxp3)-expressing regulatory T cells are key mediators of peripheral tolerance suppressing undesirable immune responses. Ectopic expression of Foxp3 confers regulatory T cell phenotype to conventional T cells, lending itself to therapeutic use in the prevention of autoimmunity and transplant rejection. Here, we show that adoptive transfer of polyclonal, wild-type T cells transduced with an inducible form of Foxp3 (iFoxp3) can be used to suppress immune responses on demand. In contrast to Foxp3-transduced cells, iFoxp3-transduced cells home "correctly" into secondary lymphoid organs, where they expand and participate in immune responses. Upon induction of iFoxp3, the cells assume regulatory T cell phenotype and start to suppress the response they initially partook in without causing systemic immunosuppression. We used this approach to suppress collagen-induced arthritis, in which conventional Foxp3-transduced cells failed to show any effect. This provides us with a generally applicable strategy to specifically halt immune responses on demand without prior knowledge of the antigens involved.


Asunto(s)
Artritis Experimental/inmunología , Linfocitos T CD4-Positivos/virología , Factores de Transcripción Forkhead/metabolismo , Terapia de Inmunosupresión , Linfocitos T Reguladores/inmunología , Transducción Genética , Traslado Adoptivo , Animales , Artritis Experimental/inducido químicamente , Linfocitos T CD4-Positivos/inmunología , Colágeno/administración & dosificación , Factores de Transcripción Forkhead/genética , Humanos , Virus de la Leucemia Murina/genética , Activación de Linfocitos , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos DBA , Ratones SCID , Linfocitos T Reguladores/citología
9.
Eur J Immunol ; 39(5): 1188-202, 2009 May.
Artículo en Inglés | MEDLINE | ID: mdl-19404987

RESUMEN

Intra vital microscopy and whole-body imaging promise to revolutionize how we study the immune system. They compel by the intrinsic beauty of the images obtained and the undeniable direct biological relevance of the observations. However, it is important to remember that in many cases, fundamental insights into the underlying biological processes have already been obtained using ex vivo reductionist approaches. Indeed, it is likely that with the advent of microfluidics, new and exciting avenues will open up for ex vivo experimentation. Here, we give a brief but comprehensive overview of the various imaging techniques available, their relative strengths and shortcomings and how these tools have been used to get us to where we are today. The challenge for the future will be to apply the most suitable technology and to integrate the findings across various imaging disciplines to build a unified, comprehensive "big picture" of the immune system.


Asunto(s)
Sistema Inmunológico/fisiología , Técnicas Inmunológicas , Alergia e Inmunología , Humanos , Microfluídica/métodos , Microscopía/métodos , Tomografía/métodos
10.
JCI Insight ; 2(3): e89160, 2017 02 09.
Artículo en Inglés | MEDLINE | ID: mdl-28194435

RESUMEN

Tregs can adopt a catabolic metabolic program with increased capacity for fatty acid oxidation-fueled oxidative phosphorylation (OXPHOS). It is unclear why this form of metabolism is favored in Tregs and, more specifically, whether this program represents an adaptation to the environment and developmental cues or is "hardwired" by Foxp3. Here we show, using metabolic analysis and an unbiased mass spectroscopy-based proteomics approach, that Foxp3 is both necessary and sufficient to program Treg-increased respiratory capacity and Tregs' increased ability to utilize fatty acids to fuel oxidative phosphorylation. Foxp3 drives upregulation of components of all the electron transport complexes, increasing their activity and ATP generation by oxidative phosphorylation. Increased fatty acid ß-oxidation also results in selective protection of Foxp3+ cells from fatty acid-induced cell death. This observation may provide novel targets for modulating Treg function or selection therapeutically.


Asunto(s)
Ácidos Grasos/metabolismo , Factores de Transcripción Forkhead/metabolismo , Proteómica/métodos , Linfocitos T Reguladores/metabolismo , Adenosina Trifosfato/metabolismo , Núcleo Celular/metabolismo , Femenino , Humanos , Metabolismo de los Lípidos , Espectrometría de Masas , Fosforilación Oxidativa , Regulación hacia Arriba
11.
J Mol Med (Berl) ; 83(2): 88-96, 2005 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-15605274

RESUMEN

In solid organ transplantation the recipient immune system recognises foreign alloantigens expressed by the graft. This results in an immune attack of the transplanted organ leading to rejection, which can be prevented only by therapeutic immunosuppression. During pregnancy the fetus should also be rejected by the maternal immune system, since it expresses antigens derived from the father. Whilst the immune system retains the ability to respond to foreign antigen, tolerance mechanisms ensure that inappropriate responses against self-antigen are prevented. Maternal immune aggression directed against the fetus is partly inhibited by peripheral tolerance mechanisms that act locally to deplete cells capable of attacking the fetus. Other local mechanisms inhibit the pathways that cause tissue damage after immune activation. Recent studies in mice and humans indicate that the maternal immune system undergoes a more systemic change that promotes materno-fetal tolerance. Naturally occurring regulatory T cells, which are commonly associated with maintaining tolerance to self-antigens, can also suppress maternal allo-responses targeted against the fetus. We review the mechanisms that mediate materno-fetal tolerance, with particular emphasis on changes in regulatory T cell function during pregnancy and discuss their implications.


Asunto(s)
Feto/inmunología , Tolerancia Inmunológica/inmunología , Terapia de Inmunosupresión , Embarazo/inmunología , Femenino , Rechazo de Injerto/inmunología , Humanos , Linfocitos T/inmunología , Trasplante Homólogo
12.
Immunobiology ; 220(8): 1025-9, 2015 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-25770018

RESUMEN

Regulatory T cells (Treg) influence the development of autoimmunity and their use is increasingly proposed for clinical applications. The well-characterized suppressive potential of Treg frequently leads to the assumption that Treg presence in prevailing numbers is indicative of immunosuppression. We hypothesized that this assumption may be false. We examined models of three different diseases caused by organ-specific autoimmune responses: primary biliary cirrhosis, atherosclerosis and rheumatoid arthritis (RA). We examined indicators of relative abundance of Treg compared to pro-inflammatory T cells, during peak inflammation. In all cases, the results were compatible with a relative enrichment of Treg at the site of inflammation or its most proximal draining lymph node. Conversely, in healthy mice or mice successfully protected from disease via a Treg-mediated mechanism, the data did not suggest that any Treg accumulation was occurring. This counter-intuitive finding may appear to be at odds with the immunosuppressive nature of Treg. Yet extensive previous studies in RA show that an accumulation of Treg occurs at peak inflammation, albeit without resulting in suppression, as the Treg suppressive function is overcome by the cytokine-rich environment. We suggest that this is a ubiquitous feature of autoimmune inflammation. Treg abundance in patient samples is increasingly used as an indicator of a state of immunosuppression. We conclude that this strategy should be revisited as it may potentially be a source of misinterpretation.


Asunto(s)
Artritis/inmunología , Aterosclerosis/inmunología , Enfermedades Autoinmunes/inmunología , Inflamación/inmunología , Cirrosis Hepática Biliar/inmunología , Linfocitos T Reguladores/inmunología , Animales , Proliferación Celular , Dieta Aterogénica/efectos adversos , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Femenino , Humanos , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Receptores de LDL/genética
13.
Biol Direct ; 10: 14, 2015 Apr 03.
Artículo en Inglés | MEDLINE | ID: mdl-25886751

RESUMEN

BACKGROUND: CD4(+) T cells are key regulators of the adaptive immune system and can be divided into T helper (Th) cells and regulatory T (Treg) cells. During an immune response Th cells mature from a naive state into one of several effector subtypes that exhibit distinct functions. The transcriptional mechanisms that underlie the specific functional identity of CD4(+) T cells are not fully understood. RESULTS: To assist investigations into the transcriptional identity and regulatory processes of these cells we performed mRNA-sequencing on three murine T helper subtypes (Th1, Th2 and Th17) as well as on splenic Treg cells and induced Treg (iTreg) cells. Our integrated analysis of this dataset revealed the gene expression changes associated with these related but distinct cellular identities. Each cell subtype differentially expresses a wealth of 'subtype upregulated' genes, some of which are well known whilst others promise new insights into signalling processes and transcriptional regulation. We show that hundreds of genes are regulated purely by alternative splicing to extend our knowledge of the role of post-transcriptional regulation in cell differentiation. CONCLUSIONS: This CD4(+) transcriptome atlas provides a valuable resource for the study of CD4(+) T cell populations. To facilitate its use by others, we have made the data available in an easily accessible online resource at www.th-express.org.


Asunto(s)
Regulación de la Expresión Génica , Linfocitos T Colaboradores-Inductores/citología , Linfocitos T Reguladores/citología , Células Th17/citología , Transcriptoma , Empalme Alternativo , Animales , Diferenciación Celular , Análisis por Conglomerados , Citometría de Flujo , Perfilación de la Expresión Génica , Sistema Inmunológico , Ratones , Ratones Endogámicos C57BL , Análisis de Componente Principal , Isoformas de Proteínas/genética , ARN Mensajero/metabolismo , Análisis de Secuencia de ARN , Transducción de Señal , Regulación hacia Arriba
14.
Front Immunol ; 3: 113, 2012.
Artículo en Inglés | MEDLINE | ID: mdl-22590469

RESUMEN

The immune system has the ability to suppress undesirable responses, such as those against commensal bacteria, food, and paternal antigens in placenta pregnancy. The lineage-specific transcription factor Foxp3 orchestrates the development and function of regulatory T cells underlying this immunological tolerance. Despite the crucial role of Foxp3 in supporting immune homeostasis, little is known about its origin, evolution, and species conservation. We explore these questions using comparative genomics, structural modeling, and functional analyses. Our data reveal that key gain-of-function events occurred during the evolution of Foxp3 in higher vertebrates. We identify key conserved residues in its forkhead domain and show a detailed analysis of the N-terminal region of Foxp3, which is only conserved in mammals. These components are under purifying selection, and our mutational analyses demonstrate that they are essential for Foxp3 function. Our study points to critical functional adaptations in immune tolerance among higher vertebrates, and suggests that Foxp3-mediated transcriptional mechanisms emerged during mammalian evolution as a stepwise gain of functional domains that enabled Foxp3 to interact with a multitude of interaction partners.

15.
Methods Mol Biol ; 707: 83-101, 2011.
Artículo en Inglés | MEDLINE | ID: mdl-21287331

RESUMEN

The decision to launch an immune response is made during the interaction of helper T cells and regulatory T cells with dendritic cells. Recognition of antigen leads to formation of immunological synapses at the interface between the cells and to activation of the T cells. The length of interaction between the T cells and dendritic cells influences the functional outcome. We have shown that in the absence of proinflammatory stimuli, regulatory T cells and naive helper T cells interact differently with dendritic cells. Neuropilin-1, which is expressed by most regulatory T cells but not naive helper T cells, promotes prolonged interactions with immature dendritic cells, resulting in higher sensitivity to limiting amounts of antigen. We tracked T cell-dendritic cell interactions in real-time using time-lapse microscopy, assessed synapse formation by immunofluorescence, and measured regulatory T cell activation by dendritic cells using suppression assays.


Asunto(s)
Células Dendríticas/citología , Células Dendríticas/metabolismo , Microscopía Confocal/métodos , Linfocitos T Reguladores/citología , Linfocitos T Reguladores/metabolismo , Animales , Ratones
16.
PLoS One ; 6(4): e18670, 2011 Apr 07.
Artículo en Inglés | MEDLINE | ID: mdl-21490927

RESUMEN

Expression of the lineage-specific DNA-binding factor Foxp3 controls the development and function of naturally occurring regulatory T cells. Foxp3 has been shown to interact with a multitude of transcriptional regulators including NFAT, NF-κB (p65), Runx1 and RORγt, as well as the histone modification enzymes TIP60, HDAC7 and HDAC9. The sum of these interactions is believed to cause the change in the transcriptional program of regulatory T cells. Here we show that Foxp3 directly or as part of a multimeric complex engages with the NF-κB component c-Rel. We demonstrate that the N-terminal region of Foxp3 is required for the binding of c-Rel, but not NFAT. Conversely, deletion of the forkhead domain causes a loss of interaction with NFAT, but not c-Rel. Our findings are of particular interest, as c-Rel is crucial for the induction of Foxp3 in regulatory T cells during thymic development, but has to be repressed in mature regulatory T cells to maintain their suppressive phenotype.


Asunto(s)
Factores de Transcripción Forkhead/metabolismo , FN-kappa B/metabolismo , Proteínas Proto-Oncogénicas c-rel/metabolismo , Western Blotting , Línea Celular , Núcleo Celular/metabolismo , Factores de Transcripción Forkhead/genética , Humanos , FN-kappa B/genética , Factores de Transcripción NFATC/metabolismo , Unión Proteica , Transporte de Proteínas , Proteínas Proto-Oncogénicas c-rel/genética
17.
J Reprod Immunol ; 90(1): 35-40, 2011 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-21632118

RESUMEN

Galectins are proteins with the ability to bind ß-galactosides through a conserved carbohydrate recognition domain. Galectin-1 exerts its biological effects by binding glycan ligands on proteins involved in cell adhesion and growth regulation. Galectin-1 inhibits trophoblast cell proliferation and induces syncytium formation. Its down-regulation in the syncytiotrophoblast has been associated with early pregnancy loss. In the choriocarcinoma-derived BeWo cells the galectin-1 induced growth inhibition is apoptosis-independent, but rather appears to be mediated by binding to cell surface receptors, such as the receptor tyrosine kinases REarranged during Transfection (RET) and Janus Kinase (JAK) 2 as well as vascular endothelial growth factor receptor 3. On the syncytiotrophoblast and extravillous trophoblast galectin-1 binds the Thomsen-Friedenreich disaccharide on mucin-1. The cell differentiation processes induced by binding to these receptors ultimately lead to the inhibition of proliferation and syncytium formation.


Asunto(s)
Diferenciación Celular , Galectina 1/metabolismo , Transducción de Señal , Trofoblastos/metabolismo , Adhesión Celular/fisiología , Proliferación Celular , Femenino , Galactósidos/metabolismo , Células Gigantes/metabolismo , Humanos , Janus Quinasa 2/metabolismo , Embarazo , Proteínas Tirosina Quinasas Receptoras/metabolismo , Trofoblastos/citología , Receptor 3 de Factores de Crecimiento Endotelial Vascular/metabolismo
19.
PLoS One ; 2(4): e382, 2007 Apr 18.
Artículo en Inglés | MEDLINE | ID: mdl-17440618

RESUMEN

BACKGROUND: Naturally occurring Foxp3(+)regulatory T cells play an important role in the inhibition of an immunological attack of the fetus. As implantation of the fetus poses an immediate antigenic challenge, the immune system has to prepare itself for this event prior to implantation. METHODOLOGY AND PRINCIPAL FINDINGS: Here, we show using quantitative RT-PCR and flow cytometry that regulatory T cells accumulate in the uterus not only during pregnancy, but also every time the female becomes fertile. Their periodic accumulation is accompanied by matching fluctuations in uterine expression of several chemokines, which have been shown to play a role in the recruitment and retention of regulatory T cells. CONCLUSIONS/SIGNIFICANCE: The data lead us to propose that every time a female approaches estrus, regulatory T cells start to accumulate in the uterus in preparation for a possible implantation event. Once pregnancy is established, those regulatory T cells that have seen alloantigen need to be retained at their site of action. Whilst several chemokines appear to be involved in the recruitment and/or retention of regulatory T cells during estrus, in pregnancy this role appears to be taken over by CCL4.


Asunto(s)
Implantación del Embrión , Linfocitos T Reguladores/inmunología , Útero/inmunología , Quimiocinas/metabolismo , Femenino , Humanos , Embarazo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Útero/metabolismo
20.
Am J Reprod Immunol ; 58(3): 238-54, 2007 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-17681041

RESUMEN

PROBLEM: Is the concept of maternal tolerance preventing rejection of the semi-allogeneic 'fetal allograft' still valid? METHOD OF STUDY: Compilation of expert reviews of literature and recent advances in research on indoleamine-2,3 dioxygenase (IDO), regulatory T cells and galectin-1. RESULTS AND CONCLUSION: A role for IDO in pregnancy success remains speculative, but solid data exist to support a role for Treg cells, and for galectin-1 in induction and action of Treg cells. Just as several signals may need to be simultaneously present to induce Th1 cytokine-triggered abortions, more than 1 signal may need to be simultaneously present to prevent rejection and ensure success. Both complement and coagulation pathways appear necessary for embryo execution.


Asunto(s)
Embrión de Mamíferos/inmunología , Galectina 1/fisiología , Tolerancia Inmunológica/fisiología , Indolamina-Pirrol 2,3,-Dioxigenasa/fisiología , Embarazo , Transducción de Señal/fisiología , Linfocitos T Reguladores/inmunología , Femenino , Rechazo de Injerto , Humanos
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