RESUMEN
Type 2 immunity helps protect the host from infection, but it also plays key roles in tissue homeostasis, metabolism, and repair. Unfortunately, inappropriate type 2 immune reactions may lead to allergy and asthma. Group 2 innate lymphoid cells (ILC2s) in the lungs respond rapidly to local environmental cues, such as the release of epithelium-derived type 2 initiator cytokines/alarmins, producing type 2 effector cytokines such as IL-4, IL-5, and IL-13 in response to tissue damage and infection. ILC2s are associated with the severity of allergic asthma, and experimental models of lung inflammation have shown how they act as playmakers, receiving signals variously from stromal and immune cells as well as the nervous system and then distributing cytokine cues to elicit type 2 immune effector functions and potentiate CD4+ T helper cell activation, both of which characterize the pathology of allergic asthma. Recent breakthroughs identifying stromal- and neuronal-derived microenvironmental cues that regulate ILC2s, along with studies recognizing the potential plasticity of ILC2s, have improved our understanding of the immunoregulation of asthma and opened new avenues for drug discovery.
Asunto(s)
Asma , Hipersensibilidad , Animales , Asma/etiología , Humanos , Inmunidad Innata , Interleucina-13 , LinfocitosRESUMEN
Migration and homing of immune cells are critical for immune surveillance. Trafficking is mediated by combinations of adhesion and chemokine receptors that guide immune cells, in response to chemokine signals, to specific locations within tissues and the lymphatic system to support tissue-localized immune reactions and systemic immunity1,2. Here we show that disruption of leukaemia inhibitory factor (LIF) production from group 2 innate lymphoid cells (ILC2s) prevents immune cells leaving the lungs to migrate to the lymph nodes (LNs). In the absence of LIF, viral infection leads to plasmacytoid dendritic cells (pDCs) becoming retained in the lungs where they improve tissue-localized, antiviral immunity, whereas chronic pulmonary allergen challenge leads to marked immune cell accumulation and the formation of tertiary lymphoid structures in the lung. In both cases immune cells fail to migrate to the lymphatics, leading to highly compromised LN reactions. Mechanistically, ILC2-derived LIF induces the production of the chemokine CCL21 from lymphatic endothelial cells lining the pulmonary lymphatic vessels, thus licensing the homing of CCR7+ immune cells (including dendritic cells) to LNs. Consequently, ILC2-derived LIF dictates the egress of immune cells from the lungs to regulate tissue-localized versus systemic immunity and the balance between allergen and viral responsiveness in the lungs.
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Movimiento Celular , Inmunidad Innata , Factor Inhibidor de Leucemia , Pulmón , Linfocitos , Animales , Femenino , Masculino , Ratones , Alérgenos/inmunología , Movimiento Celular/inmunología , Quimiocina CCL21/metabolismo , Quimiocina CCL21/inmunología , Células Dendríticas/citología , Células Dendríticas/inmunología , Células Endoteliales/inmunología , Células Endoteliales/metabolismo , Inmunidad Innata/inmunología , Factor Inhibidor de Leucemia/metabolismo , Factor Inhibidor de Leucemia/inmunología , Pulmón/inmunología , Pulmón/virología , Ganglios Linfáticos/citología , Ganglios Linfáticos/inmunología , Vasos Linfáticos/citología , Vasos Linfáticos/inmunología , Vasos Linfáticos/metabolismo , Linfocitos/clasificación , Linfocitos/citología , Linfocitos/inmunología , Ratones Endogámicos C57BL , Receptores CCR7/metabolismo , Receptores CCR7/inmunologíaRESUMEN
Homeostasis of the immune system depends on the proper function of regulatory T cells (T(reg) cells). Compromised suppressive activity of T(reg) cells leads to autoimmune disease and graft rejection and promotes anti-tumor immunity. Here we report a previously unrecognized requirement for the serine-threonine phosphatase PP2A in the function of T(reg) cells. T(reg) cells exhibited high PP2A activity, and T(reg) cell-specific ablation of the PP2A complex resulted in a severe, multi-organ, lymphoproliferative autoimmune disorder. Mass spectrometry revealed that PP2A associated with components of the mTOR metabolic-checkpoint kinase pathway and suppressed the activity of the mTORC1 complex. In the absence of PP2A, T(reg) cells altered their metabolic and cytokine profile and were unable to suppress effector immune responses. Therefore, PP2A is required for the function of T(reg) cells and the prevention of autoimmunity.
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Enfermedades Autoinmunes/inmunología , Trastornos Linfoproliferativos/inmunología , Proteína Fosfatasa 2/inmunología , Linfocitos T Reguladores/inmunología , Animales , Enfermedades Autoinmunes/genética , Enfermedades Autoinmunes/metabolismo , Autoinmunidad/genética , Autoinmunidad/inmunología , Células Cultivadas , Ceramidas/inmunología , Ceramidas/metabolismo , Femenino , Citometría de Flujo , Humanos , Immunoblotting , Células Jurkat , Trastornos Linfoproliferativos/genética , Trastornos Linfoproliferativos/metabolismo , Masculino , Diana Mecanicista del Complejo 1 de la Rapamicina , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Complejos Multiproteicos/inmunología , Complejos Multiproteicos/metabolismo , Fosforilación/inmunología , Proteína Fosfatasa 2/genética , Proteína Fosfatasa 2/metabolismo , Transducción de Señal/genética , Transducción de Señal/inmunología , Linfocitos T Reguladores/metabolismo , Serina-Treonina Quinasas TOR/inmunología , Serina-Treonina Quinasas TOR/metabolismoRESUMEN
Innate lymphoid cells (ILCs) play strategic roles in tissue homeostasis and immunity. ILCs arise from lymphoid progenitors undergoing lineage restriction and the development of specialized ILC subsets. We generated "5x polychromILC" transcription factor reporter mice to delineate ILC precursor states by revealing the multifaceted expression of key ILC-associated transcription factors (Id2, Bcl11b, Gata3, RORγt, and RORα) during ILC development in the bone marrow. This approach allowed previously unattained enrichment of rare progenitor subsets and revealed hitherto unappreciated ILC precursor heterogeneity. In vivo and in vitro assays identified precursors with potential to generate all ILC subsets and natural killer (NK) cells, and also permitted discrimination of elusive ILC3 bone marrow antecedents. Single-cell gene expression analysis identified a discrete ILC2-committed population and delineated transition states between early progenitors and a highly heterogeneous ILC1, ILC3, and NK precursor cell cluster. This diversity might facilitate greater lineage potential upon progenitor recruitment to peripheral tissues.
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Médula Ósea/inmunología , Subgrupos Linfocitarios/fisiología , Linfocitos/fisiología , Células Progenitoras Linfoides/fisiología , Factores de Transcripción/metabolismo , Animales , Diferenciación Celular , Línea Celular , Linaje de la Célula , Regulación del Desarrollo de la Expresión Génica , Genes Reporteros , Inmunidad Innata , Células Asesinas Naturales/inmunología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Análisis de la Célula Individual , Factores de Transcripción/genéticaRESUMEN
Activated CD8+ T cells directly kill target cells. Therefore, the regulation of their function is central to avoiding immunopathology. Mechanisms that curb effector functions in CD4+ and CD8+ T cells are mostly shared, yet important differences occur. Here, we focus on the control of CD8+ T cell activity and discuss the importance of a poorly understood aspect of tolerance that directly impairs engagement of target cells: the downregulation of CD8. We contextualize this process and propose that it represents a key element during CD8+ T cell modulation.
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Linfocitos T CD8-positivos , Tolerancia Inmunológica , Animales , Humanos , Linfocitos T CD4-Positivos/inmunología , Antígenos CD8/metabolismo , Antígenos CD8/inmunología , Linfocitos T CD8-positivos/inmunología , Regulación hacia Abajo/inmunología , Activación de Linfocitos/inmunologíaRESUMEN
Sepsis is a complex condition of inflammatory and immune dysregulation, triggered by severe infection. In survivors, chronic inflammation and immune dysregulation linger, facilitating the emergence of infections. CD8 dysfunction contributes to immunosuppression in sepsis survivors. We devised an animal model that enabled us to identify and analyze CD8-intrinsic defects induced by sepsis. We adoptively transferred CD45.1 CD8 OT-I T cells into CD45.2 congenic mice and subjected them to cecal ligature and puncture, to induce abdominal sepsis. One month later, we isolated the transferred CD8 cells. Surface marker expression confirmed they had not been activated through the TCR. CD8 OT-I T cells isolated from septic (or sham-operated) mice were transferred to second recipients, which were challenged with OVA-expressing Listeria monocytogenes. We compared effector capacities between OT-I cells exposed to sepsis and control cells. Naive mice that received OT-I cells exposed to sepsis had higher bacterial burden and a shorter survival when challenged with OVA-expressing L. monocytogenes. OT-I cells isolated from septic mice produced less IFN-γ but had conserved activation, expansion potential, and cytotoxic function. We observed lower transcript levels of IFN-γ and of the long noncoding RNA Ifng-as1, a local regulator of the epigenetic landscape, in cells exposed to sepsis. Accordingly, local abundance of a histone modification characteristic of active promoter regions was reduced in sepsis-exposed CD8 T cells. Our results identify a mechanism through which inflammation in the context of sepsis affects CD8 T cell function intrinsically.
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Linfocitos T CD8-positivos , Cromatina , Interferón gamma , Listeria monocytogenes , Sepsis , Animales , Ratones , Traslado Adoptivo , Linfocitos T CD8-positivos/inmunología , Cromatina/inmunología , Cromatina/metabolismo , Modelos Animales de Enfermedad , Interferón gamma/inmunología , Listeria monocytogenes/inmunología , Listeriosis/inmunología , Activación de Linfocitos/inmunología , Ratones Endogámicos C57BL , Sepsis/inmunologíaRESUMEN
The development of innate lymphoid cell (ILC) transcription factor reporter mice has shown a previously unexpected complexity in ILC hematopoiesis. Using novel polychromic mice to achieve higher phenotypic resolution, we have characterized bone marrow progenitors that are committed to the group 1 ILC lineage. These common ILC1/NK cell progenitors (ILC1/NKP), which we call "aceNKPs", are defined as lineage-Id2+IL-7Rα+CD25-α4ß7-NKG2A/C/E+Bcl11b-. In vitro, aceNKPs differentiate into group 1 ILCs, including NK-like cells that express Eomes without the requirement for IL-15, and produce IFN-γ and perforin upon IL-15 stimulation. Following reconstitution of Rag2-/-Il2rg-/- hosts, aceNKPs give rise to a spectrum of mature ILC1/NK cells (regardless of their tissue location) that cannot be clearly segregated into the traditional ILC1 and NK subsets, suggesting that group 1 ILCs constitute a dynamic continuum of ILCs that can develop from a common progenitor. In addition, aceNKP-derived ILC1/NK cells effectively ameliorate tumor burden in a model of lung metastasis, where they acquired a cytotoxic NK cell phenotype. Our results identify the primary ILC1/NK progenitor that lacks ILC2 or ILC3 potential and is strictly committed to ILC1/NK cell production irrespective of tissue homing.
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Inmunidad Innata , Interleucina-15 , Animales , Ratones , Interleucina-15/genética , Células Asesinas Naturales , Perforina , Factores de Transcripción , Proteínas Represoras , Proteínas Supresoras de TumorRESUMEN
Cryptocurrency markets have attracted many interest for global investors because of their novelty, wide on-line availability, increasing capitalization, and potential profits. In the econophysics tradition, we show that many of the most available cryptocurrencies have return statistics that do not follow Gaussian distributions, instead following heavy-tailed distributions. Entropy measures are applied, showing that portfolio diversification is a reasonable practice for decreasing return uncertainty.
RESUMEN
CD8 T cells can kill malignant cells in an antigen-specific manner. However, anti-tumoral responses are usually limited by suppressive factors that curb the effector responses of tumor-infiltrating CD8 T cells. Therapeutic strategies to overcome intra-tumoral T cell suppression, for example immune checkpoint inhibition, have been clinically effective in patients with cancer. Here, we provide data that demonstrates that GK-1, a peptide derived from the parasite Taenia crassiceps, promotes an anti-melanoma CD8 T cell response with heightened effector characteristics that leads to an increased amount of tumor-infiltrating CD44+ IFN-γ-producing CD8 T cells. The response induced by GK-1 was associated with a reduction in the expression of PD-1 and PD-L1 on tumor-infiltrating CD8 and dendritic cells, respectively, effects that led to a dramatic decrease in tumor burden. Our results suggest that the immunomodulatory properties of GK-1 may promote a CD8 T cell response that may be therapeutically useful in the setting of cancer.
Asunto(s)
Antígeno B7-H1/efectos de los fármacos , Linfocitos T CD8-positivos/efectos de los fármacos , Células Dendríticas/efectos de los fármacos , Linfocitos Infiltrantes de Tumor/efectos de los fármacos , Melanoma Experimental/inmunología , Péptidos Cíclicos/farmacología , Receptor de Muerte Celular Programada 1/efectos de los fármacos , Neoplasias Cutáneas/inmunología , Microambiente Tumoral/efectos de los fármacos , Traslado Adoptivo , Animales , Antígeno B7-H1/inmunología , Linfocitos T CD8-positivos/inmunología , Células Dendríticas/inmunología , Regulación hacia Abajo , Receptores de Hialuranos/inmunología , Interferón gamma/inmunología , Linfocitos Infiltrantes de Tumor/inmunología , Ratones , Ratones Endogámicos C57BL , Receptor de Muerte Celular Programada 1/inmunología , Linfocitos T/trasplante , Taenia , Microambiente Tumoral/inmunologíaRESUMEN
TCR-αß(+) double negative (DN) T cells (CD3(+) TCR-αß(+) CD4(-) CD8(-) NK1.1(-) CD49b(-) ) represent a minor heterogeneous population in healthy humans and mice. These cells have been ascribed pro-inflammatory and regulatory capacities and are known to expand during the course of several autoimmune diseases. Importantly, previous studies have shown that self-reactive CD8(+) T cells become DN after activation by self-antigens, suggesting that self-reactive T cells may exist within the DN T-cell population. Here, we demonstrate that programmed cell death 1 (PD-1) expression in unmanipulated mice identifies a subset of DN T cells with expression of activation-associated markers and a phenotype that strongly suggests they are derived from self-reactive CD8(+) cells. We also found that, within DN T cells, the PD-1(+) subset generates the majority of pro-inflammatory cytokines. Finally, using a TCR-activation reporter mouse (Nur77-GFP), we confirmed that in the steady-state PD-1(+) DN T cells engage endogenous antigens in healthy mice. In conclusion, we provide evidence that indicates that the PD-1(+) fraction of DN T cells represents self-reactive cells.
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Autoinmunidad , Antígenos CD4/metabolismo , Antígenos CD8/metabolismo , Activación de Linfocitos/inmunología , Receptor de Muerte Celular Programada 1/metabolismo , Receptores de Antígenos de Linfocitos T alfa-beta/metabolismo , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismo , Animales , Autoantígenos/metabolismo , Biomarcadores , Células Cultivadas , Citocinas/metabolismo , Expresión Génica , Inmunofenotipificación , Inflamación/inmunología , Inflamación/metabolismo , Mediadores de Inflamación/metabolismo , Ratones , Ratones Noqueados , Fenotipo , Receptor de Muerte Celular Programada 1/genéticaRESUMEN
TCR-αß(+) double-negative (DN; CD4(-)CD8(-)) T cells represent a poorly understood cellular subset suggested to contribute to the pathogenesis of the autoimmune disease systemic lupus erythematosus. DN T cells have been proposed to derive from CD8(+) cells. However, the conditions that govern the loss of CD8 expression after Ag encounter are unknown. In this study, we tracked the fate of CD8 T cells from transgenic TCR mice exposed to their cognate Ags as self or in the context of infection. We demonstrate that CD8 T cells lose CD8 expression and become DN only when cognate Ag is sensed as self. This process is restricted to tissues where the Ag is present. We also show that DN T cells derived from self-reactive CD8 cells express the inhibitory molecules PD-1 and Helios. These molecules identify a subset of DN T cells in normal mice. A similar population expands when CD8 T cells from repertoires enriched in self-reactive cells (Aire-deficient) are transferred into cognate hosts. Collectively, our data suggest that a subset of DN T cells, identified by the expression of PD-1 and Helios, represent self-reactive cells. Our results provide an explanation for the origin of DN T cells and introduce CD8 loss as a process associated with self-Ag encounter.
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Linfocitos T CD8-positivos/citología , Linfocitos T CD8-positivos/inmunología , Proteínas de Unión al ADN/metabolismo , Receptor de Muerte Celular Programada 1/metabolismo , Receptores de Antígenos de Linfocitos T alfa-beta/metabolismo , Subgrupos de Linfocitos T/citología , Subgrupos de Linfocitos T/metabolismo , Factores de Transcripción/metabolismo , Animales , Ratones , Ratones Desnudos , Receptores de Antígenos de Linfocitos T alfa-beta/inmunología , Subgrupos de Linfocitos T/inmunologíaRESUMEN
The immune-regulatory cytokine IL-10 plays a central role during innate and adaptive immune responses. IL-10 is elevated in the serum and tissues of patients with systemic lupus erythematosus (SLE), an autoimmune disorder characterized by autoantibody production, immune-complex formation, and altered cytokine expression. Because of its B cell-promoting effects, IL-10 may contribute to autoantibody production and tissue damage in SLE. We aimed to determine molecular events governing T cell-derived IL-10 expression in health and disease. We link reduced DNA methylation of the IL10 gene with increased recruitment of Stat family transcription factors. Stat3 and Stat5 recruitment to the IL10 promoter and an intronic enhancer regulate gene expression. Both Stat3 and Stat5 mediate trans-activation and epigenetic remodeling of IL10 through their interaction with the histone acetyltransferase p300. In T cells from SLE patients, activation of Stat3 is increased, resulting in enhanced recruitment to regulatory regions and competitive replacement of Stat5, subsequently promoting IL-10 expression. A complete understanding of the molecular events governing cytokine expression will provide new treatment options in autoimmune disorders, including SLE. The observation that altered activation of Stat3 influences IL-10 expression in T cells from SLE patients offers molecular targets in the search for novel target-directed treatment options.
Asunto(s)
Ensamble y Desensamble de Cromatina/genética , Interleucina-10/genética , Lupus Eritematoso Sistémico/genética , Lupus Eritematoso Sistémico/inmunología , Factor de Transcripción STAT3/metabolismo , Linfocitos T/metabolismo , Activación Transcripcional/genética , Acetilación , Biología Computacional , Metilación de ADN/genética , Proteína p300 Asociada a E1A/metabolismo , Elementos de Facilitación Genéticos/genética , Histonas/metabolismo , Humanos , Interleucina-10/metabolismo , Lisina/metabolismo , Fosforilación , Unión Proteica , Receptores de Antígenos de Linfocitos T/metabolismo , Factor de Transcripción STAT5/metabolismoRESUMEN
TCR-αß(+)CD3(+)CD4(-)CD8(-) "double negative" T cells are expanded in the peripheral blood of patients with systemic lupus erythematosus (SLE) and lupus-prone mice. Double negative T cells have been claimed to derive from CD8(+) cells that down-regulate CD8 co-receptors and acquire a distinct effector phenotype that includes the expression of proinflammatory cytokines. This, along with the fact that double negative T cells have been documented in inflamed organs, suggests that they may contribute to disease expression and tissue damage. We recently linked the transcription factor cAMP responsive element modulator (CREM) α, which is expressed at increased levels in T cells from SLE patients and lupus prone MRL/lpr mice, with trans-repression of a region syntenic to the murine CD8b promoter. However, the exact molecular mechanisms that result in a stable silencing of both CD8A and CD8B genes remain elusive. Here, we demonstrate that CREMα orchestrates epigenetic remodeling of the CD8 cluster through the recruitment of DNA methyltransferase (DNMT) 3a and histone methyltransferase G9a. Thus, we propose that CREMα is essential for the expansion of double negative T cells in SLE. CREMα blockade may have therapeutic value in autoimmune disorders with DN T cell expansion.
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Complejo CD3 , Antígenos CD8/biosíntesis , Ensamble y Desensamble de Cromatina , Modulador del Elemento de Respuesta al AMP Cíclico/metabolismo , Lupus Eritematoso Sistémico/metabolismo , Linfocitos T/metabolismo , Animales , Antígenos CD8/genética , Modulador del Elemento de Respuesta al AMP Cíclico/genética , ADN (Citosina-5-)-Metiltransferasas/genética , ADN (Citosina-5-)-Metiltransferasas/metabolismo , ADN Metiltransferasa 3A , Femenino , Silenciador del Gen , Antígenos de Histocompatibilidad/genética , Antígenos de Histocompatibilidad/metabolismo , N-Metiltransferasa de Histona-Lisina/genética , N-Metiltransferasa de Histona-Lisina/metabolismo , Humanos , Lupus Eritematoso Sistémico/genética , Lupus Eritematoso Sistémico/patología , Masculino , Ratones , Ratones Endogámicos MRL lpr , Linfocitos T/patologíaRESUMEN
Innate lymphoid cells (ILCs) are critical in maintaining tissue homeostasis, and during infection and inflammation. Here we identify, by using combinatorial reporter mice, a rare ILC progenitor (ILCP) population, resident to the small intestinal lamina propria (siLP) in adult mice. Transfer of siLP-ILCP into recipients generates group 1 ILCs (including ILC1 and NK cells), ILC2s and ILC3s within the intestinal microenvironment, but almost exclusively group 1 ILCs in the liver, lung and spleen. Single cell gene expression analysis and high dimensional spectral cytometry analysis of the siLP-ILCPs and ILC progeny indicate that the phenotype of the group 1 ILC progeny is also influenced by the tissue microenvironment. Thus, a local pool of siLP-ILCP can contribute to pan-ILC generation in the intestinal microenvironment but has more restricted potential in other tissues, with a greater propensity than bone marrow-derived ILCPs to favour ILC1 and ILC3 production. Therefore, ILCP potential is influenced by both tissue of origin and the microenvironment during development. This may provide additional flexibility during the tuning of immune reactions.
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Inmunidad Innata , Mucosa Intestinal , Células Progenitoras Linfoides , Ratones Endogámicos C57BL , Animales , Ratones , Mucosa Intestinal/inmunología , Mucosa Intestinal/citología , Células Progenitoras Linfoides/citología , Células Progenitoras Linfoides/metabolismo , Células Progenitoras Linfoides/inmunología , Microambiente Celular/inmunología , Linfocitos/inmunología , Intestino Delgado/inmunología , Intestino Delgado/citología , Femenino , MasculinoRESUMEN
OBJECTIVE: Variants in STAT4 are associated with systemic lupus erythematosus (SLE) and other autoimmune diseases. We undertook this study to investigate how disease-associated variants affect STAT4 expression, in particular in CD4+ T cells where STAT4 plays an essential role. METHODS: We compared Th1 differentiation between naive CD4+ T cells from healthy donors homozygous for the risk (R/R) or nonrisk (NR/NR) alleles. We analyzed epigenetic marks in STAT4 and evaluated the relevance of its third intron, assessed the consequences of Stat4 overexpression in vivo in mice, and analyzed the effects of the STAT4 genotype in patients with lupus nephritis. RESULTS: Naive CD4+ T cells from NR/NR healthy donors down-regulated STAT4 in response to interleukin-12 (IL-12). In contrast, cells from R/R healthy donors maintained high levels. R/R cells exhibited a higher abundance of transcriptionally active STAT4 and increased interferon-γ production. Accordingly, R/R healthy donors exhibited a stronger induction of local active enhancer marks. Genetic editing confirmed the presence of a negative regulatory region in the STAT4 third intron, where most of the SLE-associated STAT4 single-nucleotide polymorphisms (SNPs) are located. In vivo forced expression demonstrated that increases in Stat4 levels in T cells enhanced glomerulonephritis in mice. Accordingly, the R/R genotype was associated with suboptimal response to treatment and with worse clinical outcomes in patients with proliferative lupus nephritis. CONCLUSION: The SLE-associated STAT4 haplotype correlates with an abnormal IL-12-mediated STAT4 transcriptional regulation. Carriers of the risk variant exhibit exaggerated CD4+ proinflammatory capacities that, in the context of SLE, contribute to more severe disease. R/R patients may benefit from blockade of the IL-12/STAT4 pathway.
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Lupus Eritematoso Sistémico , Nefritis Lúpica , Animales , Ratones , Linfocitos T CD4-Positivos/metabolismo , Regulación hacia Abajo , Haplotipos , Interferón gamma/genética , Interleucina-12 , Lupus Eritematoso Sistémico/genética , Nefritis Lúpica/genética , Polimorfismo de Nucleótido Simple , Factor de Transcripción STAT4/genética , HumanosRESUMEN
The neuroactive steroid estradiol reduces reactive astroglia after brain injury by mechanisms similar to those involved in the regulation of reactive gliosis by endocannabinoids. In this study, we have explored whether cannabinoid receptors are involved in the effects of estradiol on reactive astroglia. To test this hypothesis, the effects of estradiol, the cannabinoid CB1 antagonist/inverse agonist AM251, and the cannabinoid CB2 antagonist/inverse agonist AM630 were assessed in the cerebral cortex of male rats after a stab wound brain injury. Estradiol reduced the number of vimentin immunoreactive astrocytes and the number of glial fibrillary acidic protein immunoreactive astrocytes in the proximity of the wound. The effect of estradiol was significantly inhibited by the administration of either CB1 or CB2 receptor antagonists. The effect of estradiol may be in part mediated by alterations in endocannabinoid signaling because the hormone increased in the injured cerebral cortex the messenger RNA levels of CB2 receptors and of some of the enzymes involved in the synthesis and metabolism of endocannabinoids. These findings suggest that estradiol may decrease reactive astroglia in the injured brain by regulating the activity of the endocannabinoid system.
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Lesiones Encefálicas/patología , Corteza Cerebral/efectos de los fármacos , Corteza Cerebral/patología , Estradiol/farmacología , Gliosis/patología , Gliosis/prevención & control , Receptores de Cannabinoides/efectos de los fármacos , Animales , Moduladores de Receptores de Cannabinoides/biosíntesis , Cannabinoides/farmacología , Proteína Ácida Fibrilar de la Glía/metabolismo , Inmunohistoquímica , Indoles/farmacología , Masculino , Piperidinas/farmacología , Pirazoles/farmacología , ARN Mensajero/biosíntesis , ARN Mensajero/genética , Ratas , Ratas Wistar , Receptor Cannabinoide CB1/agonistas , Receptor Cannabinoide CB2/agonistas , Técnicas Estereotáxicas , Fijación del Tejido , Vimentina/farmacología , Heridas Punzantes/patologíaRESUMEN
Colorectal cancer (CRC) is the second leading cause of cancer-related death worldwide, and is largely refractory to current immunotherapeutic interventions. The lack of efficacy of existing cancer immunotherapies in CRC reflects the complex nature of the unique intestinal immune environment, which serves to maintain barrier integrity against pathogens and harmful environmental stimuli while sustaining host-microbe symbiosis during homeostasis. With their expression by barrier epithelial cells, the cytokines interleukin-25 (IL-25) and IL-33 play key roles in intestinal immune responses, and have been associated with inappropriate allergic reactions, autoimmune diseases and cancer pathology. Studies in the past decade have begun to uncover the important roles of IL-25 and IL-33 in shaping the CRC tumour immune microenvironment, where they may promote or inhibit tumorigenesis depending on the specific CRC subtype. Notably, both IL-25 and IL-33 have been shown to act on group 2 innate lymphoid cells (ILC2s), but can also stimulate an array of other innate and adaptive immune cell types. Though sometimes their functions can overlap they can also produce distinct phenotypes dependent on the differential distribution of their receptor expression. Furthermore, both IL-25 and IL-33 modulate pathways previously known to contribute to CRC tumorigenesis, including angiogenesis, tumour stemness, invasion and metastasis. Here, we review our current understanding of IL-25 and IL-33 in CRC tumorigenesis, with specific focus on dissecting their individual function in the context of distinct subtypes of CRC, and the potential prospects for targeting these pathways in CRC immunotherapy.
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Neoplasias Colorrectales , Interleucina-33 , Humanos , Interleucina-17/metabolismo , Inmunidad Innata , Neoplasias Colorrectales/metabolismo , Linfocitos/metabolismo , Carcinogénesis , Transformación Celular Neoplásica/genética , Citocinas , Microambiente TumoralRESUMEN
Adaptive immune responses rely on the proliferation of T lymphocytes able to recognize and eliminate pathogens. The magnitude and duration of the expansion of activated T cell clones are finely regulated to minimize immunopathology and avoid autoimmunity. In patients with rheumatic autoimmune diseases, such as systemic lupus erythematosus and rheumatoid arthritis, activated lymphocytes survive and exert effector functions for prolonged periods, defying the mechanisms that normally curb their capacities during acute and chronic infections. Here, we review the molecular mechanisms that limit the duration of immune responses in health and discuss the factors that alter such regulation in the setting of systemic lupus erythematosus and rheumatoid arthritis. We highlight defects that could contribute to the development and progression of autoimmune disease and describe how chronic inflammation can alter the regulation of activated lymphocyte survival, promoting its perpetuation. These concepts might contribute to the understanding of the mechanisms that underlie the chronicity of inflammation in the context of autoimmunity.
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Artritis Reumatoide , Enfermedades Autoinmunes , Lupus Eritematoso Sistémico , Enfermedades Reumáticas , Autoinmunidad , Supervivencia Celular , Humanos , Inflamación , Linfocitos TRESUMEN
Interleukin-25 (IL-25) and group 2 innate lymphoid cells (ILC2s) defend the host against intestinal helminth infection and are associated with inappropriate allergic reactions. IL-33-activated ILC2s were previously found to augment protective tissue-specific pancreatic cancer immunity. Here, we showed that intestinal IL-25-activated ILC2s created an innate cancer-permissive microenvironment. Colorectal cancer (CRC) patients with higher tumor IL25 expression had reduced survival and increased IL-25R-expressing tumor-resident ILC2s and myeloid-derived suppressor cells (MDSCs) associated with impaired antitumor responses. Ablation of IL-25 signaling reduced tumors, virtually doubling life expectancy in an Apc mutation-driven model of spontaneous intestinal tumorigenesis. Mechanistically, IL-25 promoted intratumoral ILC2s, which sustained tumor-infiltrating MDSCs to suppress antitumor immunity. Therapeutic antibody-mediated blockade of IL-25 signaling decreased intratumoral ILC2s, MDSCs, and adenoma/adenocarcinoma while increasing antitumor adaptive T cell and interferon-γ (IFN-γ)-mediated immunity. Thus, the roles of innate epithelium-derived cytokines IL-25 and IL-33 as well as ILC2s in cancer cannot be generalized. The protumoral nature of the IL-25-ILC2 axis in CRC highlights this pathway as a potential therapeutic target against CRC.
Asunto(s)
Proteína de la Poliposis Adenomatosa del Colon/genética , Interleucina-33 , Células Supresoras de Origen Mieloide , Carcinogénesis , Humanos , Inmunidad Innata , Interleucina-17 , Interleucina-33/genética , Linfocitos , Mutación , Microambiente TumoralRESUMEN
Activation of self-reactive CD8+ T cells induces a peripheral tolerance mechanism that involves loss of CD8 expression. Because genetic deficiency of Fas and Fasl causes the accumulation of double-negative (DN; CD3+ TCR-αß+ CD4- CD8-) T cells that have been proposed to derive from CD8+ cells, we decided to explore the role of Fas and FasL in self-antigen-induced CD8 downregulation. To this end, we quantified Fas and FasL induction by different stimuli and analyzed the effects of Fas/FasL deficiency during a protective immune response and after exposure to self-antigens. Our data describes how Fas and FasL upregulation differs depending on the setting of CD8 T cell activation and demonstrates that Fas/FasL signaling maintains CD8 expression during repetitive antigen stimulation and following self-antigen encounter. Together, our results reveal an unexpected role of Fas/FasL signaling and offer a new insight into the role of these molecules in the regulation of immune tolerance.