RESUMEN
Regulatory T cells (Tregs) are vital for maintaining immune self-tolerance, and their impaired function leads to autoimmune disease. Mutations in FoxP3, the master transcriptional regulator of Tregs, leads to immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome in humans and the early lethal "scurfy" phenotype with multi-organ autoimmune disease in mice. We recently identified serine/arginine-rich splicing factor 1 (SRSF1) as an indispensable regulator of Treg homeostasis and function. Intriguingly, Treg-conditional SRSF1-deficient mice exhibit early lethal systemic autoimmunity with multi-organ inflammation reminiscent of the scurfy mice. Importantly, SRSF1 is decreased in T cells from patients with the autoimmune disease systemic lupus erythematosus (SLE), and low SRSF1 levels inversely correlate with disease severity. Given that the Treg-specific deficiency of SRSF1 causes similarly profound autoimmune disease outcomes in mice as the deficiency/mutation in FoxP3, we aimed to evaluate the genes and molecular pathways controlled by these two indispensable regulatory proteins. We performed comparative bioinformatic analyses of transcriptomic profiles of Tregs from Srsf1-knockout mice and two Foxp3 mutant mice--the FoxP3-deficient ΔFoxp3 and the Foxp3 M370I mutant mice. We identified 132 differentially expressed genes (DEGs) unique to Srsf1-ko Tregs, 503 DEGs unique to Foxp3 M370I Tregs, and 1367 DEGs unique to ΔFoxp3 Tregs. Gene set enrichment and pathway analysis of DEGs unique to Srsf1-ko Tregs indicate that SRSF1 controls cytokine and immune response pathways. Conversely, FoxP3 controls pathways involved in DNA replication and cell cycle. Besides the distinct gene signatures, we identified only 30 shared genes between all three Treg mutants, mostly contributing to cytokine and immune defense pathways. Prominent genes included the chemokines CXCR6 and CCL1 and the checkpoint inhibitors FASLG and PDCD1. Thus, we demonstrate that SRSF1 and FoxP3 control common and distinct molecular pathways implicated in autoimmunity. Our analyses suggest that SRSF1 controls crucial immune functions in Tregs contributing to immune tolerance, and perturbations in its levels lead to systemic autoimmunity via mechanisms that are largely distinct from FoxP3.
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Diabetes Mellitus Tipo 1 , Lupus Eritematoso Sistémico , Factores de Empalme Serina-Arginina , Animales , Humanos , Ratones , Citocinas/metabolismo , Factores de Transcripción Forkhead , Lupus Eritematoso Sistémico/metabolismo , Ratones Noqueados , Factores de Empalme de ARN/metabolismo , Factores de Empalme Serina-Arginina/genética , Linfocitos T ReguladoresRESUMEN
Cytotoxic CD8 T cells are crucial for the host antigen-specific immune response to viral pathogens. Here we report the identification of an essential role for the serine/arginine-rich splicing factor (SRSF) 1 in CD8 T cell homeostasis and function. Specifically, SRSF1 is necessary for the maintenance of normal CD8 T lymphocyte numbers in the lymphoid compartment, and for the proliferative capacity and cytotoxic function of CD8 T cells. Furthermore, SRSF1 is required for antigen-specific IFN-γ cytokine responses in a viral infection challenge in mice. Transcriptomics analyses of Srsf1-deficient T cells reveal that SRSF1 controls proliferation, MAP kinase signaling and IFN signaling pathways. Mechanistically, SRSF1 controls the expression and activity of the Mnk2/p38-MAPK axis at the molecular level. Our findings reveal previously unrecognized roles for SRSF1 in the physiology and function of cytotoxic CD8 T lymphocytes and a potential molecular mechanism in viral immunopathogenesis.
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Linfocitos T CD8-positivos , Citocinas , Factores de Empalme Serina-Arginina/inmunología , Animales , Arginina , Linfocitos T CD8-positivos/metabolismo , Citocinas/metabolismo , Inmunidad , Ratones , Factores de Empalme de ARN , Serina , Factores de Empalme Serina-Arginina/genética , Factores de Empalme Serina-Arginina/metabolismoRESUMEN
Systemic autoimmune diseases are characterized by hyperactive effector T cells (Teffs), aberrant cytokines and chemokines, and dysfunctional regulatory T cells (Tregs). We previously uncovered new roles for serine/arginine-rich splicing factor 1 (SRSF1) in the control of genes involved in T cell signaling and cytokine production in human T cells. SRSF1 levels are decreased in T cells from patients with systemic lupus erythematosus (SLE), and low levels correlate with severe disease. Moreover, T cell-conditional Srsf1-deficient mice recapitulate the autoimmune phenotype, exhibiting CD4 T cell hyperactivity, dysfunctional Tregs, systemic autoimmunity, and tissue inflammation. However, the role of SRSF1 in controlling molecular programs in Teffs and Tregs and how these pathways are implicated in autoimmunity is not known. Here, by comparative bioinformatics analysis, we demonstrate that SRSF1 controls largely distinct gene programs in Tregs and Teffs in vivo. SRSF1 regulates 189 differentially expressed genes (DEGs) unique to Tregs, 582 DEGs unique to Teffs, and 29 DEGs shared between both. Shared genes included IL-17A, IL-17F, CSF1, CXCL10, and CXCR4, and were highly enriched for inflammatory response and cytokine-cytokine receptor interaction pathways. SRSF1 controls distinct pathways in Tregs, which include chemokine signaling and immune cell differentiation, compared with pathways in Teffs, which include cytokine production, T cell homeostasis, and activation. We identified putative mRNA binding targets of SRSF1 which include CSF1, CXCL10, and IL-17F. Finally, comparisons with transcriptomics profiles from lupus-prone MRL/lpr mice reveal that SRSF1 controls genes and pathways implicated in autoimmune disease. The target genes of SRSF1 and putative binding targets we discovered, have known roles in systemic autoimmunity. Our findings suggest that SRSF1 controls distinct molecular pathways in Tregs and Teffs and aberrant SRSF1 levels may contribute to their dysfunction and immunopathogenesis of systemic autoimmune disease.
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Enfermedades Autoinmunes/inmunología , Autoinmunidad/inmunología , Factores de Empalme de ARN/inmunología , Factores de Empalme Serina-Arginina/inmunología , Linfocitos T Reguladores/inmunología , Animales , Linfocitos T CD4-Positivos/inmunología , Diferenciación Celular/inmunología , Citocinas/inmunología , Inflamación/inmunología , Lupus Eritematoso Sistémico/inmunología , Ratones , Ratones Noqueados , ARN Mensajero/inmunología , Transducción de Señal/inmunología , Transcriptoma/inmunologíaRESUMEN
The ability of regulatory T (Treg) cells to control the immune response and limit the development of autoimmune diseases is determined by distinct molecular processes, which are not fully understood. We show here that serine/arginine-rich splicing factor 1 (SRSF1), which is decreased in T cells from patients with systemic lupus erythematosus, is necessary for the homeostasis and proper function of Treg cells, because its conditional absence in these cells leads to profound autoimmunity and organ inflammation by elevating the glycolytic metabolism and mTORC1 activity and the production of proinflammatory cytokines. Our data reveal a molecular mechanism that controls Treg cell plasticity and offer insights into the pathogenesis of autoimmune disease.
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Homeostasis , Factores de Empalme Serina-Arginina/metabolismo , Linfocitos T/metabolismo , Animales , Plasticidad de la Célula , Supervivencia Celular , Eliminación de Gen , Glucólisis , Heterocigoto , Inflamación/patología , Ratones Endogámicos C57BL , Ratones Noqueados , Fenotipo , Factores de Empalme Serina-Arginina/deficiencia , Sirolimus/farmacología , Linfocitos T Reguladores/inmunología , Transcriptoma/genéticaRESUMEN
Acute and chronic kidney failure is common in hospitalized patients with COVID-19, yet the mechanism of injury and predisposing factors remain poorly understood. We investigated the role of complement activation by determining the levels of deposited complement components (C1q, C3, FH, C5b-9) and immunoglobulin along with the expression levels of the injury-associated molecules spleen tyrosine kinase (Syk), mucin-1 (MUC1) and calcium/calmodulin-dependent protein kinase IV (CaMK4) in the kidney tissues of people who succumbed to COVID-19. We report increased deposition of C1q, C3, C5b-9, total immunoglobulin, and high expression levels of Syk, MUC1 and CaMK4 in the kidneys of COVID-19 patients. Our study provides strong rationale for the expansion of trials involving the use of inhibitors of these molecules, in particular C1q, C3, Syk, MUC1 and CaMK4 to treat patients with COVID-19.
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COVID-19/metabolismo , Proteínas del Sistema Complemento/metabolismo , Riñón/metabolismo , Mucina-1/metabolismo , SARS-CoV-2 , Quinasa Syk/metabolismo , Anciano , Anciano de 80 o más Años , COVID-19/patología , Proteína Quinasa Tipo 4 Dependiente de Calcio Calmodulina/genética , Proteína Quinasa Tipo 4 Dependiente de Calcio Calmodulina/metabolismo , Proteínas del Sistema Complemento/genética , Resultado Fatal , Femenino , Regulación de la Expresión Génica , Humanos , Masculino , Persona de Mediana Edad , Mucina-1/genética , Quinasa Syk/genéticaRESUMEN
OBJECTIVE: Autoimmune diseases affect women disproportionately more than men. Estrogen is implicated in immune cell dysfunction, yet its precise molecular roles are not fully known. We recently identified new roles for serine/arginine-rich splicing factor 1 (SRSF1) in T cell function and autoimmunity. SRSF1 levels are decreased in T cells from patients with systemic lupus erythematosus (SLE) and are associated with active disease and comorbidity. However, the molecular mechanisms that control SRSF1 expression are unknown. Srsf1 messenger RNA (mRNA) has a long 3'-untranslated region (3'-UTR), suggesting posttranscriptional control. This study was undertaken to investigate the role of estrogen and posttranscriptional mechanisms of SRSF1 regulation in T cells and SLE. METHODS: In silico bioinformatics analysis of Srsf1-3'-UTR revealed multiple microRNA (miRNA; miR)-binding sites. Additional screening and literature searches narrowed down hsa-miR-10b-5p for further study. Peripheral blood T cells from healthy individuals and SLE patients were evaluated for mRNA and miRNA expression by quantitative reverse transcription-polymerase chain reaction, and SRSF1 protein levels were assessed by immunoblotting. T cells were cultured with ß-estradiol, and transient transfections were used to overexpress miRNAs. Luciferase assays were used to measure 3'-UTR activity. RESULTS: We demonstrated that estrogen increased hsa-miR-10b-5p expression in human T cells, and hsa-miR-10b-5p down-regulated SRSF1 protein expression. Mechanistically, hsa-mir-10b-5p regulated SRSF1 posttranscriptionally via control of its 3'-UTR activity. Importantly, hsa-miR-10b-5p expression levels were elevated in T cells from healthy women compared to healthy men and also elevated in T cells from SLE patients. CONCLUSION: We identified a previously unrecognized molecular link between estrogen and gene regulation in immune cells, with potential relevance to systemic autoimmune disease.
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Regulación hacia Abajo/efectos de los fármacos , Estradiol/farmacología , Lupus Eritematoso Sistémico/metabolismo , MicroARNs/metabolismo , Factores de Empalme Serina-Arginina/metabolismo , Linfocitos T/efectos de los fármacos , Adulto , Anciano , Simulación por Computador , Femenino , Células HEK293 , Humanos , Lupus Eritematoso Sistémico/genética , Activación de Linfocitos , Masculino , MicroARNs/genética , Persona de Mediana Edad , Factores de Empalme Serina-Arginina/genética , Linfocitos T/metabolismo , Adulto JovenRESUMEN
Lung inflammation and damage is prominent in people infected with SARS-Cov-2 and a major determinant of morbidity and mortality. We report the deposition of complement components in the lungs of people who succumbed to COVID-19 consistent with the activation of the classical and the alternative pathways. Our study provides strong rationale for the expansion of trials involving the use of complement inhibitors to treat patients with COVID-19.
Asunto(s)
COVID-19/inmunología , Activación de Complemento/inmunología , Vía Alternativa del Complemento/inmunología , Lesión Pulmonar/inmunología , Anciano , Anciano de 80 o más Años , COVID-19/complicaciones , Inactivadores del Complemento/farmacología , Inactivadores del Complemento/uso terapéutico , Células Epiteliales/metabolismo , Células Epiteliales/patología , Femenino , Humanos , Inmunohistoquímica , Pulmón/diagnóstico por imagen , Pulmón/inmunología , Pulmón/patología , Lesión Pulmonar/complicaciones , Lesión Pulmonar/patología , Lesión Pulmonar/virología , Masculino , Persona de Mediana EdadRESUMEN
OBJECTIVE: CD4 T helper 1 (Th1) cells producing IFN-γ contribute to inflammatory responses in the pathogenesis of SLE and lupus nephritis. Moreover, elevated serum type II IFN levels precede the appearance of type I IFNs and autoantibodies in patient years before clinical diagnosis. However, the molecules and mechanisms that control this inflammatory response in SLE remain unclear. Serine/arginine-rich splicing factor 1 (SRSF1) is decreased in T cells from SLE patients, and restrains T cell hyperactivity and systemic autoimmunity. Our objective here was to evaluate the role of SRSF1 in IFN-γ production, Th1 differentiation and experimental nephritis. METHODS: T cell-conditional Srsf1-knockout mice were used to study nephrotoxic serum-induced nephritis and evaluate IFN-γ production and Th1 differentiation by flow cytometry. RNA sequencing was used to assess transcriptomics profiles. RhoH was silenced by siRNA transfections in human T cells by electroporation. RhoH and SRSF1 protein levels were assessed by immunoblots. RESULTS: Deletion of Srsf1 in T cells led to increased Th1 differentiation and exacerbated nephrotoxic serum nephritis. The expression levels of RhoH are decreased in Srsf1-deficient T cells, and silencing RhoH in human T cells leads to increased production of IFN-γ. Furthermore, RhoH expression was decreased and directly correlated with SRSF1 in T cells from SLE patients. CONCLUSION: Our study uncovers a previously unrecognized role of SRSF1 in restraining IFN-γ production and Th1 differentiation through the control of RhoH. Reduced expression of SRSF1 may contribute to pathogenesis of autoimmune-related nephritis through these molecular mechanisms.
Asunto(s)
Diferenciación Celular/fisiología , Interferón gamma/metabolismo , Nefritis Lúpica/genética , Factores de Empalme Serina-Arginina/genética , Células TH1/metabolismo , Factores de Transcripción/metabolismo , Proteínas de Unión al GTP rho/metabolismo , Animales , Citometría de Flujo , Humanos , Nefritis Lúpica/inmunología , Nefritis Lúpica/metabolismo , Ratones , Ratones Noqueados , Factores de Empalme Serina-Arginina/metabolismo , Células TH1/inmunologíaRESUMEN
The SARS-CoV-2 novel coronavirus has caused the COVID-19 pandemic with over 35 million cases and over a million deaths worldwide as of early October 2020. The populations most affected are the elderly and especially those with underlying comorbidities. In terms of race and ethnicity, black and hispanic populations are affected at disproportionately higher rates. Individuals with underlying conditions that cause an immune-compromised state are considered vulnerable to this infection. The immune response is an important determinant in viral infections including coronaviruses, not only in the antiviral defense but also in the disease progression, severity, and clinical outcomes of COVID-19. Systemic lupus erythematosus is a chronic autoimmune disease which also disproportionately afflicts black and hispanic populations. In lupus patients, an aberrant immune response is characterized by the presence of circulating autoantibodies, lymphopenia, aberrant T cells, and proinflammatory cytokines along with defective regulatory mechanisms, leading to immune-mediated damage to tissues. Lupus patients are often treated with immune-suppressants and therefore are immune-compromised and more susceptible to infections and may be vulnerable to coronavirus infection. While the anti-viral immune response is important to protect from coronavirus infection, an uncontrolled proinflammatory cytokine response can lead to cytokine storm which causes damage to the lungs and other organs, causing significant morbidity and mortality. Better understanding of the underlying immune response and therapeutic strategies in lupus and COVID-19 is important to guide management of this deadly infectious disease in the context of lupus and vice-versa.
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COVID-19/inmunología , Lupus Eritematoso Sistémico/inmunología , SARS-CoV-2/fisiología , Animales , COVID-19/genética , COVID-19/virología , Humanos , Lupus Eritematoso Sistémico/tratamiento farmacológico , Lupus Eritematoso Sistémico/genética , SARS-CoV-2/genética , SARS-CoV-2/inmunología , Tratamiento Farmacológico de COVID-19RESUMEN
The novel severe acute respiratory syndrome coronavirus 2, the cause of the coronavirus disease 2019 (COVID-19) pandemic, has ravaged the world, with over 22 million total cases and over 770,000 deaths worldwide as of August 18, 2020. While the elderly are most severely affected, implicating an age bias, a striking factor in the demographics of this deadly disease is the gender bias, with higher numbers of cases, greater disease severity, and higher death rates among men than women across the lifespan. While pre-existing comorbidities and social, behavioral, and lifestyle factors contribute to this bias, biological factors underlying the host immune response may be crucial contributors. Women mount stronger immune responses to infections and vaccinations and outlive men. Sex-based biological factors underlying the immune response are therefore important determinants of susceptibility to infections, disease outcomes, and mortality. Despite this, gender is a profoundly understudied and often overlooked variable in research related to the immune response and infectious diseases, and it is largely ignored in drug and vaccine clinical trials. Understanding these factors will not only help better understand the pathogenesis of COVID-19, but it will also guide the design of effective therapies and vaccine strategies for gender-based personalized medicine. This review focuses on sex-based differences in genes, sex hormones, and the microbiome underlying the host immune response and their relevance to infections with a focus on coronaviruses.
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Betacoronavirus/inmunología , Infecciones por Coronavirus/inmunología , Infecciones por Coronavirus/mortalidad , Interacciones Huésped-Patógeno/inmunología , Neumonía Viral/inmunología , Neumonía Viral/mortalidad , Inmunidad Adaptativa/genética , COVID-19 , Infecciones por Coronavirus/virología , Femenino , Predisposición Genética a la Enfermedad , Hormonas Esteroides Gonadales/inmunología , Interacciones Huésped-Patógeno/genética , Humanos , Inmunidad Innata/genética , Masculino , Microbiota/inmunología , Pandemias , Neumonía Viral/virología , SARS-CoV-2 , Factores SexualesRESUMEN
Mature double negative (DN) T cells are a population of αß T cells that lack CD4 and CD8 coreceptors and contribute to systemic lupus erythematosus (SLE). The splenic marginal zone macrophages (MZMs) are important for establishing immune tolerance, and loss of their number or function contributes to the progression of SLE. Here we show that loss of MZMs impairs the tolerogenic clearance of apoptotic cells and alters the serum cytokine profile, which in turn provokes the generation of DN T cells from self-reactive CD8+ T cells. Increased Ki67 expression, narrowed TCR V-beta repertoire usage and diluted T-cell receptor excision circles confirm that DN T cells from lupus-prone mice and patients with SLE undergo clonal proliferation and expansion in a self-antigen dependent manner, which supports the shared mechanisms for their generation. Collectively, our results provide a link between the loss of MZMs and the expansion of DN T cells, and indicate possible strategies to prevent the development of SLE.
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Autoantígenos/inmunología , Interleucina-17/metabolismo , Lupus Eritematoso Sistémico/inmunología , Subgrupos de Linfocitos T/inmunología , Traslado Adoptivo , Animales , Autoantígenos/metabolismo , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Femenino , Humanos , Tolerancia Inmunológica , Antígeno Ki-67/inmunología , Antígeno Ki-67/metabolismo , Lupus Eritematoso Sistémico/sangre , Macrófagos/inmunología , Ratones , Ratones Noqueados , Receptores de Antígenos de Linfocitos T alfa-beta/metabolismo , Subgrupos de Linfocitos T/metabolismoRESUMEN
OBJECTIVE: Lymphopenia is a frequent clinical manifestation and risk factor for infections in SLE, but the underlying mechanisms are not fully understood. We previously identified novel roles for the RNA-binding protein serine arginine-rich splicing factor 1 (SRSF1) in the control of genes involved in signalling and cytokine production in human T cells. SRSF1 is decreased in T cells from patients with SLE and associates with severe disease. Because SRSF1 controls the expression of apoptosis-related genes, we hypothesized that SRSF1 controls T cell homeostasis and, when reduced, leads to lymphopenia. METHODS: We evaluated SRSF1 expression in T cells from SLE patients by immunoblots and analysed its correlation with clinical parameters. T cell conditional Srsf1 knockout mice were used to evaluate lymphoid cells and apoptosis by flow cytometry. Quantitative PCR and immunoblots were used to assess Bcl-xL mRNA and protein expression. SRSF1 overexpression was performed by transient transfections by electroporation. RESULTS: We found that low SRSF1 levels correlated with lymphopenia in SLE patients. Selective deletion of Srsf1 in T cells in mice led to T cell lymphopenia, with increased apoptosis and decreased expression of the anti-apoptotic Bcl-xL. Lower SRSF1 expression correlated with low Bcl-xL levels in T cells and lower Bcl-xL levels associated with lymphopenia in SLE patients. Importantly, overexpression of SRSF1 rescued survival of T cells from patients with SLE. CONCLUSION: Our studies uncovered a previously unrecognized role for SRSF1 in the control of T cell homeostasis and its reduced expression as a molecular defect that contributes to lymphopenia in systemic autoimmunity.
Asunto(s)
Homeostasis/fisiología , Lupus Eritematoso Sistémico/metabolismo , Linfopenia/metabolismo , Factores de Empalme Serina-Arginina/metabolismo , Linfocitos T/metabolismo , Adulto , Animales , Femenino , Humanos , Lupus Eritematoso Sistémico/sangre , Lupus Eritematoso Sistémico/genética , Activación de Linfocitos/fisiología , Linfopenia/genética , Masculino , Ratones , Ratones Noqueados , Persona de Mediana Edad , Factores de Empalme Serina-Arginina/sangre , Factores de Empalme Serina-Arginina/genética , Adulto Joven , Proteína bcl-X/genética , Proteína bcl-X/metabolismoRESUMEN
The novel coronavirus severe acute respiratory syndrome coronavirus 2 causing the Coronavirus disease (COVID-19) pandemic has ravaged the world with over 72 million total cases and over 1.6 million deaths worldwide as of early December 2020. An overwhelming preponderance of cases and deaths is observed within the elderly population, and especially in those with pre-existing conditions and comorbidities. Aging causes numerous biological changes in the immune system, which are linked to age-related illnesses and susceptibility to infectious diseases. Age-related changes influence the host immune response and therefore not only weaken the ability to fight respiratory infections but also to mount effective responses to vaccines. Immunosenescence and inflamm-aging are considered key features of the aging immune system wherein accumulation of senescent immune cells contribute to its decline and simultaneously increased inflammatory phenotypes cause immune dysfunction. Age-related quantitative and qualitative changes in the immune system affect cells and soluble mediators of both the innate and adaptive immune responses within lymphoid and non-lymphoid peripheral tissues. These changes determine not only the susceptibility to infections, but also disease progression and clinical outcomes thereafter. Furthermore, the response to therapeutics and the immune response to vaccines are influenced by age-related changes within the immune system. Therefore, better understanding of the pathophysiology of aging and the immune response will not only help understand age-related diseases but also guide targeted management strategies for deadly infectious diseases like COVID-19.
RESUMEN
Systemic lupus erythematosus (SLE) is a devastating autoimmune disease in which hyperactive T cells play a critical role. Understanding molecular mechanisms underlying the T cell hyperactivity will lead to identification of specific therapeutic targets. Serine/arginine-rich splicing factor 1 (SRSF1) is an essential RNA-binding protein that controls posttranscriptional gene expression. We have demonstrated that SRSF1 levels are aberrantly decreased in T cells from patients with SLE and that they correlate with severe disease, yet the role of SRSF1 in T cell physiology and autoimmune disease is largely unknown. Here we show that T cell-restricted Srsf1-deficient mice develop systemic autoimmunity and lupus-nephritis. Mice exhibit increased frequencies of activated/effector T cells producing proinflammatory cytokines, and an elevated T cell activation gene signature. Mechanistically, we noted increased activity of the mechanistic target of rapamycin (mTOR) pathway and reduced expression of its repressor PTEN. The mTOR complex 1 (mTORC1) inhibitor rapamycin suppressed proinflammatory cytokine production by T cells and alleviated autoimmunity in Srsf1-deficient mice. Of direct clinical relevance, PTEN levels correlated with SRSF1 in T cells from patients with SLE, and SRSF1 overexpression rescued PTEN and suppressed mTORC1 activation and proinflammatory cytokine production. Our studies reveal the role of a previously unrecognized molecule, SRSF1, in restraining T cell activation, averting the development of autoimmune disease, and acting as a potential therapeutic target for lupus.
Asunto(s)
Autoinmunidad , Factores de Empalme Serina-Arginina/fisiología , Linfocitos T/inmunología , Animales , Citocinas/biosíntesis , Humanos , Nefritis Lúpica/etiología , Activación de Linfocitos , Diana Mecanicista del Complejo 1 de la Rapamicina/fisiología , Ratones , Ratones Endogámicos C57BL , Fosfohidrolasa PTEN/análisis , Fosfohidrolasa PTEN/genética , Transducción de Señal , Sirolimus/farmacología , Serina-Treonina Quinasas TOR/fisiologíaRESUMEN
Tregs require IL-2 signaling for signal transducer and activator of transcription 5 (STAT5)-mediated induction of Foxp3. While phosphatase 2A (PP2A) is a negative regulator of IL-2 production in effector T cells and Tregs do not produce IL-2, it is not known whether PP2A controls IL-2 signaling in Tregs. To address the role of PP2A in IL-2 signaling in Tregs we studied mice engineered to lack PP2A in all Foxp3-expressing cells. We report that PP2A is required to enable Foxp3 expression and to maintain sufficient numbers of Tregs in the thymus. We show for the first time that PP2A prevents the selective loss of surface IL-2Rß and preserves IL-2R signaling potency in Tregs. The loss of IL-2Rß in thymus- and spleen-derived Tregs that lack PP2A is due to increased sheddase activity. Pan-sheddase or selective A disintegrin and metalloproteinase 10 (ADAM10) inhibition, like forced expression of IL-2Rß in PP2A-deficient Tregs restored IL-2Rß expression and signaling. Thus, PP2A restrains the sheddase activity of ADAM10 in Treg cells to prevent the cleavage of IL-2Rß from the cell surface to enable competent IL-2R signaling which is essential for Tregs development and homeostasis.
Asunto(s)
Interleucina-2/metabolismo , Proteína Fosfatasa 2/metabolismo , Receptores de Interleucina-2/metabolismo , Transducción de Señal , Linfocitos T Reguladores/metabolismo , Proteína ADAM10/metabolismo , Secretasas de la Proteína Precursora del Amiloide , Animales , Enfermedades Autoinmunes/metabolismo , Autoinmunidad , Linfocitos T CD4-Positivos/inmunología , Desintegrinas/metabolismo , Factores de Transcripción Forkhead/metabolismo , Homeostasis , Proteínas de la Membrana , Ratones , Ratones Noqueados , Proteína Fosfatasa 2/genética , Receptores de Interleucina-2/deficiencia , Factor de Transcripción STAT5/metabolismo , Bazo/patología , Timo/patologíaRESUMEN
Women have stronger immune responses to infections and vaccination than men. Paradoxically, the stronger immune response comes at a steep price, which is the high incidence of autoimmune diseases in women. The reasons why women have stronger immunity and higher incidence of autoimmunity are not clear. Besides gender, sex hormones contribute to the development and activity of the immune system, accounting for differences in gender-related immune responses. Both innate and adaptive immune systems bear receptors for sex hormones and respond to hormonal cues. This review focuses on the role of sex hormones particularly estrogen, in the adaptive immune response, in health, and autoimmune disease with an emphasis on systemic lupus erythematosus.
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Inmunidad Adaptativa/inmunología , Enfermedades Autoinmunes/inmunología , Hormonas Esteroides Gonadales/inmunología , Sistema Inmunológico/inmunología , Enfermedades Autoinmunes/metabolismo , Estrógenos/inmunología , Estrógenos/metabolismo , Femenino , Hormonas Esteroides Gonadales/metabolismo , Humanos , Sistema Inmunológico/metabolismo , Lupus Eritematoso Sistémico/inmunología , Lupus Eritematoso Sistémico/metabolismo , Masculino , Factores SexualesRESUMEN
Defective DNA methylation in T cells leads to a series of T cell abnormalities in lupus; however, the full effect of T cell lineage-specific DNA methylation on disease expression has not been explored. Here, we show that 5-azacytidine, a DNA methyltransferase inhibitor, targeted to either CD4 or CD8 T cells in mice with established disease using a nanolipogel delivery system dramatically ameliorates lupus-related pathology through distinct mechanisms. In vivo targeted delivery of 5-azacytidine into CD4 T cells favors the expansion and function of Foxp3+ Tregs, whereas targeted delivery to CD8 T cells enhances the cytotoxicity and restrains the expansion of pathogenic TCR-αß+CD4-CD8- double-negative T cells. Our results signify the importance of cell-specific inhibition of DNA methylation in the treatment of established lupus.
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Azacitidina/administración & dosificación , Metilación de ADN/efectos de los fármacos , Lupus Eritematoso Sistémico/tratamiento farmacológico , Nanoconjugados/química , Animales , Linfocitos T CD4-Positivos/efectos de los fármacos , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/metabolismo , Linfocitos T CD8-positivos/efectos de los fármacos , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Metilación de ADN/inmunología , Metilasas de Modificación del ADN/antagonistas & inhibidores , Modelos Animales de Enfermedad , Epigénesis Genética/efectos de los fármacos , Epigénesis Genética/inmunología , Femenino , Humanos , Inmunoconjugados/química , Lupus Eritematoso Sistémico/genética , Lupus Eritematoso Sistémico/inmunología , Ratones , Ratones Transgénicos , Resultado del TratamientoRESUMEN
Systemic lupus erythematosus (SLE) is a chronic multi-organ debilitating autoimmune disease, which mainly afflicts women in the reproductive years. A complex interaction of genetics, environmental factors and hormones result in the breakdown of immune tolerance to "self" leading to damage and destruction of multiple organs, such as the skin, joints, kidneys, heart and brain. Both innate and adaptive immune systems are critically involved in the misguided immune response against self-antigens. Dendritic cells, neutrophils, and innate lymphoid cells are important in initiating antigen presentation and propagating inflammation at lymphoid and peripheral tissue sites. Autoantibodies produced by B lymphocytes and immune complex deposition in vital organs contribute to tissue damage. T lymphocytes are increasingly being recognized as key contributors to disease pathogenesis. CD4 T follicular helper cells enable autoantibody production, inflammatory Th17 subsets promote inflammation, while defects in regulatory T cells lead to unchecked immune responses. A better understanding of the molecular defects including signaling events and gene regulation underlying the dysfunctional T cells in SLE is necessary to pave the path for better management, therapy, and perhaps prevention of this complex disease. In this review, we focus on the aberrations in T cell signaling in SLE and highlight therapeutic advances in this field.