RESUMEN
BACKGROUND: Testis is an immune privileged organ, which prevents the immune response against sperm antigens and inflammation. Testicular cells responsible for immune tolerance are mainly Sertoli cells, which form the blood-testis barrier and produce immunosuppressive factors. Sertoli cells prevent inflammation in the testis and maintain immune tolerance by inhibiting proliferation and inducing lymphocyte apoptosis. It has been shown that 9-cis-retinoic acid (9cRA) blocks ex vivo apoptosis of peripheral blood lymphocytes and promotes the differentiation of Treg cells in the gut. However, the role of retinoid signaling in regulating the immune privilege of the testes remains unknown. OBJECTIVE: The aim of this study was to determine whether 9cRA, acting via the retinoic acid receptors (RAR) and the retinoic X receptors (RXR), controls the immunomodulatory functions of Sertoli cells by influencing the secretion of anti-inflammatory/pro-inflammatory factors, lymphocyte physiology and Treg cell differentiation. METHODS: Experiments were performed using in vitro model of co-cultures of murine Sertoli cells and T lymphocytes. Agonists and antagonists of retinoic acid receptors were used to inhibit/stimulate retinoid signaling in Sertoli cells. RESULTS: Our results have demonstrated that 9cRA inhibits the expression of immunosuppressive genes and enhances the expression of pro-inflammatory factors in Sertoli cells and lymphocytes, increases lymphocyte viability and decreases apoptosis rate. Moreover, we have found that 9cRA blocks lymphocyte apoptosis acting through both RAR and RXR and inhibiting FasL/Fas/Caspase 8 and Bax/Bcl-2/Caspase 9 pathways. Finally, we have shown that 9cRA signaling in Sertoli cells inhibits Treg differentiation. CONCLUSION: Collectively, our results indicate that retinoid signaling negatively regulates immunologically privileged functions of Sertoli cells, crucial for ensuring male fertility. 9cRA inhibits lymphocyte apoptosis, which can be related to the development of autoimmunity, inflammation, and, in consequence, infertility.
Asunto(s)
Diferenciación Celular , Células de Sertoli , Transducción de Señal , Linfocitos T Reguladores , Tretinoina , Masculino , Animales , Células de Sertoli/metabolismo , Células de Sertoli/efectos de los fármacos , Linfocitos T Reguladores/efectos de los fármacos , Linfocitos T Reguladores/metabolismo , Linfocitos T Reguladores/inmunología , Transducción de Señal/efectos de los fármacos , Ratones , Tretinoina/farmacología , Diferenciación Celular/efectos de los fármacos , Alitretinoína/farmacología , Receptores de Ácido Retinoico/metabolismo , Apoptosis/efectos de los fármacos , Técnicas de Cocultivo , Ratones Endogámicos C57BL , Células Cultivadas , Inmunomodulación/efectos de los fármacosRESUMEN
BACKGROUND: In multiple sclerosis (MS), the imbalance between T helper (Th)-17 cells and regulatory T (Treg) cells are critical in autoimmune central nervous system (CNS) inflammation and demyelination. Experimental autoimmune encephalomyelitis (EAE) is an established mouse MS model and simulates MS at diverse levels. OBJECTIVES: This study aims at investigating the impact of anlotinib on the clinical severity of EAE and CD4+ T cell differentiation. MATERIALS AND METHODS: EAE-induced mice were treated with water (control) or 6 mg/kg anlotinib by gavage daily. At the peak of EAE, histopathological examination and flow cytometry analysis of CNS-infiltrating CD4+ T cells were performed. In vitro differentiation of CD4+ T cells under different conditions was detected by flow cytometry and quantitative real-time PCR. Finally, the impacts of anlotinib on the phosphorylation of signal transducer and activator of transcription 3 (STAT3) and the transcription levels of key genes involved in Th17 and Treg differentiation were tested. RESULTS: Anlotinib attenuated the clinical severity of EAE and changed the frequencies of CNS-infiltrating CD4+ T cell subsets. Anlotinib inhibited the differentiation of Th17 cells in vitro, decreased the phosphorylation of STAT3, and reduced the expression of Rorc. Anlotinib promoted the differentiation of Treg cells and upregulated the expression levels of CD39 and CD73. DISCUSSION AND CONCLUSIONS: Anlotinib alleviated the symptoms of EAE via inhibiting the Th17 cell differentiation and promoting Treg cell differentiation. Our study provides new opportunities for the exploitation of anlotinib as a therapeutic agent for the treatment of MS.
Asunto(s)
Encefalomielitis Autoinmune Experimental , Esclerosis Múltiple , Animales , Diferenciación Celular , Modelos Animales de Enfermedad , Indoles , Ratones , Ratones Endogámicos C57BL , Quinolinas , Linfocitos T Reguladores , Células TH1 , Células Th17RESUMEN
Naïve CD4+ T cells in the periphery differentiate into regulatory T cells (Tregs) in which Foxp3 is expressed for their suppressive function. NLRP3, a pro-inflammatory molecule, is known to be involved in inflammasome activation associated with several diseases. Recently, the expression of NLRP3 in CD4+ T cells, as well as in myeloid cells, has been described; however, a role of T cell-intrinsic NLRP3 in Treg differentiation remains unknown. Here, we report that NLRP3 impeded the expression of Foxp3 independent of inflammasome activation in Tregs. NLRP3-deficient mice elevate Treg generation in various organs in the de novo pathway. NLRP3 deficiency increased the amount and suppressive activity of Treg populations, whereas NLRP3 overexpression reduced Foxp3 expression and Treg abundance. Importantly, NLRP3 interacted with Kpna2 and translocated to the nucleus from the cytoplasm under Treg-polarizing conditions. Taken together, our results identify a novel role for NLRP3 as a new negative regulator of Treg differentiation, mediated via its interaction with Kpna2 for nuclear translocation.
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Diferenciación Celular , Núcleo Celular/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Linfocitos T Reguladores/citología , Linfocitos T Reguladores/metabolismo , alfa Carioferinas/metabolismo , Animales , Femenino , Factores de Transcripción Forkhead/metabolismo , Inflamasomas/metabolismo , Ratones Endogámicos C57BL , Modelos Biológicos , Proteína con Dominio Pirina 3 de la Familia NLR/deficiencia , Transporte de ProteínasRESUMEN
Self-tolerance, the state of unresponsiveness to self-tissues/antigens, is maintained through central and peripheral tolerance mechanisms, and a breach of these mechanisms leads to autoimmune diseases. Foxp3â¯+â¯T-regulatory cells (Tregs) play an essential role in suppressing autoimmune response directed against self-antigens and thereby regulate self-tolerance. Natural Tregs are differentiated in the thymus on the basis of their higher TCR-affinity to self-antigens and migrate to the periphery where they maintain peripheral tolerance. In addition, extra-thymic differentiation of induced Tregs can occur in the periphery which can control abrupt immune responses under inflammatory conditions. A defect in Treg cell numbers and/or function is found to be associated with the development of autoimmune disease in several experimental models and human autoimmune diseases. Moreover, augmentation of Tregs has been shown to be beneficial in treating autoimmunity in preclinical models, and Treg based cellular therapy has shown initial promise in clinical trials. However, emerging studies have identified an unstable subpopulation of Tregs which expresses pro-inflammatory cytokines under both homeostatic and autoimmune conditions, as well as in ex vivo cultures. In addition, clinical translation of Treg cellular therapy is impeded by limitations such as lack of easier methods for selective expansion of Tregs and higher cost associated with GMP-facilities required for cell sorting, ex vivo expansion and infusion of ex vivo expanded Tregs. Here, we discuss the recent advances in molecular mechanisms regulating Treg differentiation, Foxp3 expression and lineage stability, the role of Tregs in the prevention of various autoimmune diseases, and critically review their clinical utility for treating human autoimmune diseases.
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Enfermedades Autoinmunes/inmunología , Autoinmunidad/inmunología , Autotolerancia/inmunología , Linfocitos T Reguladores/inmunología , Animales , Diferenciación Celular/inmunología , HumanosRESUMEN
Efferocytosis, the process of engulfing and removing apoptotic cells, plays an essential role in preserving tissue health and averting undue inflammation. While macrophages are primarily known for this task, dendritic cells (DCs) also play a significant role. This review delves into the unique contributions of various DC subsets to efferocytosis, highlighting the distinctions in how DCs and macrophages recognize and handle apoptotic cells. It further explores how efferocytosis influences DC maturation, thereby affecting immune tolerance. This underscores the pivotal role of DCs in orchestrating immune responses and sustaining immune equilibrium, providing new insights into their function in immune regulation.
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Células Dendríticas , Macrófagos , Fagocitosis , Células Dendríticas/inmunología , Humanos , Fagocitosis/inmunología , Animales , Macrófagos/inmunología , Apoptosis/inmunología , Tolerancia Inmunológica , EferocitosisRESUMEN
Rheumatoid arthritis (RA) is an autoimmune disorder characterized by chronic inflammation of the synovial joints and the dysfunction of regulatory T cells (Tregs) in the peripheral blood. Therefore, an optimal treatment strategy should aim to eliminate the inflammatory response in the joints and simultaneously restore the immune tolerance of Tregs in peripheral blood. Accordingly, we developed an efferocytosis-mimicking nanovesicle that contains three functional factors for immunomodulating of efferocytosis, including "find me" and "eat me" signals for professional (macrophage) or non-professional phagocytes (T lymphocyte), and "apoptotic metabolite" for metabolite digestion. We showed that efferocytosis-mimicking nanovesicles targeted the inflamed joints and spleen of mice with collagen-induced arthritis, further recruiting and selectively binding to macrophages and T lymphocytes to induce M2 macrophage polarization and Treg differentiation and T helper cell 17 (Th17) recession. Under systemic administration, the efferocytosis-mimicking nanovesicles effectively maintained the pro-inflammatory M1/anti-inflammatory M2 macrophage balance in joints and the Treg/Th17 imbalance in peripheral blood to prevent RA progression. This study demonstrates the potential of efferocytosis-mimicking nanovesicles for RA immunotherapy.
Asunto(s)
Artritis Reumatoide , Eferocitosis , Nanopartículas , Animales , Ratones , Artritis Experimental/inmunología , Artritis Reumatoide/inmunología , Modelos Animales de Enfermedad , Terapia de Inmunosupresión/métodos , Inflamación/inmunología , Macrófagos/inmunología , Nanopartículas/química , Linfocitos T Reguladores/inmunologíaRESUMEN
Immune responses are primarily mediated by adaptive and innate immune cells. Adaptive immune cells, such as T and B cells, evoke antigen-specific responses through the recognition of specific antigens. This antigen-specific recognition relies on the V(D)J recombination of immunoglobulin (Ig) and T cell receptor (TCR) genes mediated by recombination-activating gene (Rag)1 and Rag2 (Rag1/2). In addition, T and B cells employ cell type-specific developmental pathways during their activation processes, and the regulation of these processes is strictly regulated by the transcription factor network. Among these factors, members of the basic helix-loop-helix (bHLH) transcription factor mammalian E protein family, including E12, E47, E2-2, and HEB, orchestrate multiple adaptive immune cell development, while their antagonists, Id proteins (Id1-4), function as negative regulators. It is well established that a majority of T and B cell developmental trajectories are regulated by the transcriptional balance between E and Id proteins (the E-Id axis). E2A is critically required not only for B cell but also for T cell lineage commitment, whereas Id2 and Id3 enforce the maintenance of naïve T cells and naïve regulatory T (Treg) cells. Here, we review the current knowledge of E- and Id-protein function in T cell lineage commitment and Treg cell differentiation.
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Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico , Factores de Transcripción , Animales , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Diferenciación Celular , Hematopoyesis , Activación de Linfocitos , Mamíferos/metabolismo , Factores de Transcripción/metabolismoRESUMEN
Interleukin (IL)-33 is an alarmin factor that is highly secreted in a variety of autoimmune diseases, induces maturation of dendritic cells (DCs) and differentiation of T helper 17 (Th17) cells. As the balance between Th17 cells and regulatory T cells (Tregs) is important to maintain immune homeostasis, in this study, we investigated the effects of IL-33 on Treg cell response. We observed that direct treatment with IL-33 had no effect on Treg differentiation, whereas IL-33-matured DCs (IL33-matDCs) inhibited the differentiation of CD4+ T cells to Tregs by decreasing the expression of Foxp3. Furthermore, co-culture with IL-33-matDCs changed stable Tregs (CD25hiCD4+ Tregs) to IL-17-producing cells, whereas IL-33-matDCs had little effects on unstable Tregs (CD25loCD4+ Tregs). The stable Tregs were demonstrated to express high levels of IL-6 receptors. Blocking of IL-6 secreted from IL-33-matDCs suppressed the conversion of Tregs to Th17 cells, indicating the greater propensity to convert stable Tregs to Th17 cells is due to IL-6 signaling. Taken together, these results demonstrate that IL-33 inhibits Treg differentiation and the conversion of stable Tregs to Th17 cells via DCs.
Asunto(s)
Células Dendríticas/inmunología , Células Dendríticas/metabolismo , Interleucina-33/metabolismo , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/metabolismo , Células Th17/inmunología , Células Th17/metabolismo , Animales , Biomarcadores , Comunicación Celular , Diferenciación Celular/inmunología , Plasticidad de la Célula/inmunología , Técnicas de Cocultivo , Femenino , Inmunofenotipificación , Subunidad alfa del Receptor de Interleucina-2/metabolismo , Activación de Linfocitos/inmunología , Ratones , Transducción de Señal , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismoRESUMEN
Peripheral immune self-tolerance relies on protective mechanisms to control autoreactive T cells that escape deletion in the thymus. Suppression of autoreactive lymphocytes is necessary to avoid autoimmunity and immune cell-mediated damage of healthy tissues. An intriguing relationship has emerged between two mechanisms of peripheral tolerance-induction of anergy and Foxp3 + regulatory T (Treg) cells-and is not yet well understood. A subpopulation of autoreactive anergic CD4 T cells is a precursor of Treg cells. We now hypothesize that phenotypic and mechanistic features of Treg cells can provide insights to understand the mechanisms behind anergy-derived Treg cell differentiation. In this short review, we will highlight several inherent similarities between the anergic state in conventional CD4 T cells as compared with fully differentiated natural Foxp3 + Treg cells and then propose a model whereby modulations in metabolic programming lead to changes in DNA methylation at the Foxp3 locus to allow Foxp3 expression following the reversal of anergy.
Asunto(s)
Anergia Clonal/inmunología , Epigénesis Genética , Factores de Transcripción Forkhead/genética , Linfocitos T Reguladores/inmunología , Animales , Autoinmunidad , Linfocitos T CD4-Positivos/inmunología , Secuencia Conservada/genética , Metilación de ADN/inmunología , Epigénesis Genética/inmunología , Factores de Transcripción Forkhead/metabolismo , Humanos , Autotolerancia/inmunologíaRESUMEN
OBJECTIVE: The aim of this study was to investigate the effect of miR-133a and miR-133b on regulatory T cell (Treg) differentiation in IgA nephropathy (IgAN) through targeting forkhead box P3 (FOXP3). METHODS: Peripheral blood mononuclear cells (PBMCs) were isolated from IgAN patients (nâ¯=â¯20) and healthy controls (nâ¯=â¯20). Percentage of Tregs defined as CD4â¯+â¯CD25â¯+â¯FOXP3â¯+â¯T cells were determined by flow cytometry. The mRNA expression levels of miR-133a, miR-133b and FOXP3 were measured by real-time PCR. FOXP3 protein level was analyzed by western blotting. RESULTS: Tregs percentage in PBMCs of IgAN patients was significantly lower than that of healthy controls, whereas the expression levels of miR-133a and miR-133b in IgAN patients were dramatically higher than that in the control group. Treg percentage was negatively correlated with miR-133a and miR-133b expressions. Meanwhile, miR-133a and miR-133b modulated FOXP3 expression by detecting of its gene 3'-untranslated region. MiR-133a or miR-133b overexpression significantly decreased the % Tregs (CD4â¯+â¯CD25â¯+â¯FOXP3+) of the total CD4â¯+â¯T cells while miR-133a or miR-133b knockdown led to an opposite effect. Moreover, FOXP3 levels in IgAN patients was significantly lower than that in the control group and was negatively correlated with miR-133a and miR-133b expression. CONCLUSION: MiR-133a and miR-133b inhibited Treg differentiation in IgA nephropathy through targeting FOXP3.
Asunto(s)
Factores de Transcripción Forkhead/genética , Glomerulonefritis por IGA/genética , MicroARNs/genética , Linfocitos T Reguladores/inmunología , Adulto , Western Blotting , Estudios de Casos y Controles , Diferenciación Celular , Femenino , Citometría de Flujo , Regulación de la Expresión Génica/genética , Técnicas de Silenciamiento del Gen , Glomerulonefritis por IGA/inmunología , Humanos , Leucocitos Mononucleares/inmunología , Masculino , Persona de Mediana Edad , ARN Mensajero/genética , Reacción en Cadena en Tiempo Real de la PolimerasaRESUMEN
Regulatory T cells (Tregs) are characterized by the expression of the master transcription factor forkhead box P3 (Foxp3). Although Foxp3 expression is widely used as a marker of the Treg lineage, recent data show that the Treg fate is determined by a multifactorial signaling pathway, involving cytokines, nuclear factors, and epigenetic modifications. Foxp3 expression and the Treg phenotype can be acquired by T cells in the periphery, illustrating that the Treg fate is not necessarily conferred during thymic development. The two main Treg populations in vivo, thymic Tregs and peripheral Tregs, differ in the pathways followed for their maturation. This chapter discusses the molecular control of Treg induction, in the thymus as well as the periphery.
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Transducción de Señal , Linfocitos T Reguladores/citología , Linfocitos T Reguladores/metabolismo , Animales , Diferenciación Celular , Humanos , Timo/citologíaRESUMEN
The study was designed to test DNA Aß42 immunization in mice as alternative approach for possible active immunotherapy in Alzheimer patients. As results, we found polarized Th2 immune responses, efficient Aß42 antibody levels, and disappearance of antigen specific T cells. In-vivo TNFRSF4/25 antibody co-stimulation enhanced Aß42 specific T cell responses with initial Th2 expansion and subsequent development of Aß42 specific CD4+CD25+Foxp3+ cells. It showed that Th2 biased responses due to gene gun immunizations propagate the development of regulatory T cells. In conclusion, full-length DNA Aß42 immunization into skin results in a regulatory response with minimal risk of inflammation and autoimmunity.
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Péptidos beta-Amiloides/genética , Anticuerpos/farmacología , Citocinas/metabolismo , ADN/inmunología , Fragmentos de Péptidos/genética , Receptores OX40/inmunología , Miembro 25 de Receptores de Factores de Necrosis Tumoral/inmunología , Linfocitos T Reguladores/efectos de los fármacos , Enfermedad de Alzheimer/terapia , Péptidos beta-Amiloides/inmunología , Animales , Anticuerpos/sangre , Células Cultivadas , ADN/química , Proteínas de Unión al ADN/metabolismo , Femenino , Factores de Transcripción Forkhead/genética , Factor de Transcripción GATA3/metabolismo , Humanos , Inmunoterapia , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Transgénicos , Fragmentos de Péptidos/inmunología , Bazo/citología , Bazo/efectos de los fármacos , Bazo/metabolismo , Linfocitos T Reguladores/citología , Factores de Transcripción/metabolismoRESUMEN
The role of complement in the regulation of T cell immunity has been highlighted recently by several groups. We were prompted to reinvestigate the role of complement receptor type 1 (CR1, CD35) [corrected] in human T cells based on our earlier data showing that activated human T cells produce C3 (Torok et al. (2012) [48]) and also by results demonstrating that engagement of Membrane Cofactor Protein (MCP, CD46) induces a switch of anti-CD35-activated [corrected] helper T cells into regulatory T cells (Kemper et al. (2003) [17]). We demonstrate here that co-ligation of CD46 and CD35, [corrected] the two C3b-binding structures present on activated CD4+ human T cells significantly enhances CD25 expression, elevates granzyme B production and synergistically augments cell proliferation. The role of CR1 in the development of the Treg phenotype was further confirmed by demonstrating that its engagement enhances IL-10 production and reduces IFNγ release by the activated CD4+ T cells in the presence of excess IL-2. The functional in vivo relevance of our findings was highlighted by the immunohistochemical staining of tonsils, revealing the presence of CD4/CD35 [corrected] double positive lymphocytes mainly in the inter-follicular regions where direct contact between CD4+ T cells and B lymphocytes occurs. Regarding the in vivo relevance of the complement-dependent generation of regulatory T cells in secondary lymphoid organs we propose a scenario shown in the figure. The depicted process involves the sequential binding of locally produced C3 fragments to CD46 and CD35 [corrected] expressed on activated T cells, which - in the presence of excess IL-2 - leads to the development of Treg cells.