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1.
Annu Rev Immunol ; 39: 167-198, 2021 04 26.
Artículo en Inglés | MEDLINE | ID: mdl-33534604

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 , Linfocitos
2.
Nat Immunol ; 17(5): 556-64, 2016 May.
Artículo en Inglés | MEDLINE | ID: mdl-26974206

RESUMEN

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.


Asunto(s)
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/metabolismo
3.
Immunity ; 51(1): 104-118.e7, 2019 07 16.
Artículo en Inglés | MEDLINE | ID: mdl-31128961

RESUMEN

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.


Asunto(s)
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/genética
4.
Trends Immunol ; 45(6): 442-453, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38782625

RESUMEN

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.


Asunto(s)
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/inmunología
5.
Proc Natl Acad Sci U S A ; 119(49): e2203454119, 2022 12 06.
Artículo en Inglés | MEDLINE | ID: mdl-36442116

RESUMEN

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.


Asunto(s)
Inmunidad Innata , Interleucina-15 , Animales , Ratones , Interleucina-15/genética , Células Asesinas Naturales , Perforina , Factores de Transcripción , Proteínas Represoras , Proteínas Supresoras de Tumor
6.
Entropy (Basel) ; 24(11)2022 Nov 01.
Artículo en Inglés | MEDLINE | ID: mdl-36359673

RESUMEN

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.

7.
Clin Immunol ; 212: 108240, 2020 03.
Artículo en Inglés | MEDLINE | ID: mdl-31299381

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/inmunología
8.
Eur J Immunol ; 46(6): 1383-91, 2016 06.
Artículo en Inglés | MEDLINE | ID: mdl-27060346

RESUMEN

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.


Asunto(s)
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/genética
9.
J Immunol ; 194(9): 4207-14, 2015 May 01.
Artículo en Inglés | MEDLINE | ID: mdl-25825451

RESUMEN

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.


Asunto(s)
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/inmunología
10.
Proc Natl Acad Sci U S A ; 111(37): 13457-62, 2014 Sep 16.
Artículo en Inglés | MEDLINE | ID: mdl-25187566

RESUMEN

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/metabolismo
11.
J Biol Chem ; 289(4): 2361-70, 2014 Jan 24.
Artículo en Inglés | MEDLINE | ID: mdl-24297179

RESUMEN

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.


Asunto(s)
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/patología
12.
Arthritis Rheumatol ; 75(6): 961-972, 2023 06.
Artículo en Inglés | MEDLINE | ID: mdl-36575804

RESUMEN

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.


Asunto(s)
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 , Humanos
13.
Cereb Cortex ; 21(9): 2046-55, 2011 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-21258044

RESUMEN

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.


Asunto(s)
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/patología
14.
Front Immunol ; 13: 981479, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-36263033

RESUMEN

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.


Asunto(s)
Neoplasias Colorrectales , Interleucina-33 , Humanos , Interleucina-17/metabolismo , Inmunidad Innata , Neoplasias Colorrectales/metabolismo , Linfocitos/metabolismo , Carcinogénesis , Transformación Celular Neoplásica/genética , Citocinas , Microambiente Tumoral
15.
Nat Rev Rheumatol ; 18(4): 232-244, 2022 04.
Artículo en Inglés | MEDLINE | ID: mdl-35075294

RESUMEN

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.


Asunto(s)
Artritis Reumatoide , Enfermedades Autoinmunes , Lupus Eritematoso Sistémico , Enfermedades Reumáticas , Autoinmunidad , Supervivencia Celular , Humanos , Inflamación , Linfocitos T
16.
Sci Immunol ; 7(72): eabn0175, 2022 06 03.
Artículo en Inglés | MEDLINE | ID: mdl-35658010

RESUMEN

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 Tumoral
17.
Front Immunol ; 12: 635862, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33841416

RESUMEN

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.


Asunto(s)
Autoantígenos/metabolismo , Antígenos CD8/metabolismo , Linfocitos T CD8-positivos/metabolismo , Proteína Ligando Fas/metabolismo , Tolerancia Inmunológica , Activación de Linfocitos , Receptor fas/metabolismo , Traslado Adoptivo , Animales , Autoantígenos/inmunología , Antígenos CD8/inmunología , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/trasplante , Células Cultivadas , Regulación hacia Abajo , Proteína Ligando Fas/genética , Proteína Ligando Fas/inmunología , Cinética , Ratones Endogámicos C57BL , Ratones Transgénicos , Fenotipo , Transducción de Señal , Receptor fas/genética , Receptor fas/inmunología
18.
Mucosal Immunol ; 14(1): 26-37, 2021 01.
Artículo en Inglés | MEDLINE | ID: mdl-32457448

RESUMEN

Type-2 immunity is characterised by interleukin (IL)-4, IL-5 and IL-13, eosinophilia, mucus production, IgE, and alternatively activated macrophages (AAM). However, despite the lack of neutrophil chemoattractants such as CXCL1, neutrophils, a feature of type-1 immunity, are observed in type-2 responses. Consequently, alternative mechanisms must exist to ensure that neutrophils can contribute to type-2 immune reactions without escalation of deleterious inflammation. We now demonstrate that type-2 immune-associated neutrophil infiltration is regulated by the mouse RNase A homologue, eosinophil-associated ribonuclease 11 (Ear11), which is secreted by AAM downstream of IL-25-stimulated ILC2. Transgenic overexpression of Ear11 resulted in tissue neutrophilia, whereas Ear11-deficient mice have fewer resting tissue neutrophils, whilst other type-2 immune responses are not impaired. Notably, administration of recombinant mouse Ear11 increases neutrophil motility and recruitment. Thus, Ear11 helps maintain tissue neutrophils at homoeostasis and during type-2 reactions when chemokine-producing classically activated macrophages are infrequently elicited.


Asunto(s)
Inmunidad Innata , Linfocitos/fisiología , Activación de Macrófagos/inmunología , Macrófagos/fisiología , Infiltración Neutrófila/inmunología , Neutrófilos/fisiología , Ribonucleasas/biosíntesis , Animales , Células Dendríticas/inmunología , Células Dendríticas/metabolismo , Eosinófilos/inmunología , Eosinófilos/metabolismo , Inmunomodulación , Inmunofenotipificación , Interleucina-13/biosíntesis , Pulmón/inmunología , Pulmón/metabolismo , Pulmón/patología , Ratones , Ratones Transgénicos , Ribonucleasas/genética
19.
J Leukoc Biol ; 108(3): 851-857, 2020 09.
Artículo en Inglés | MEDLINE | ID: mdl-32052478

RESUMEN

The cellular origin of CD4- CD8- (double negative, DNT) TCR-α/ß+ T cells remains unknown. Available evidence indicates that they may derive from CD8+ T cells, but most published data have been obtained using cells that bear an invariant transgenic T cell receptor that recognizes an Ag that is not present in normal mice. Here, we have used complementary fate mapping and adoptive transfer experiments to identify the cellular lineage of origin of DNT cells in wild-type mice with a polyclonal T cell repertoire. We show that TCR-α/ß+ DNT cells can be traced back to CD8+ and CD4+ CD8+ double positive cells in the thymus. We also demonstrate that polyclonal DNT cells generated in secondary lymphoid organs proliferate upon adoptive transfer and can regain CD8 expression in lymphopenic environment. These results demonstrate the cellular origin of DNT cells and provide a conceptual framework to understand their presence in pathological circumstances.


Asunto(s)
Antígenos CD4/análisis , Antígenos CD8/análisis , Linfocitos T CD8-positivos/citología , Linfopoyesis , Receptores de Antígenos de Linfocitos T alfa-beta/análisis , Subgrupos de Linfocitos T/citología , Traslado Adoptivo , Animales , Antígenos CD8/biosíntesis , Antígenos CD8/genética , Linfocitos T CD8-positivos/clasificación , Linaje de la Célula , Tejido Linfoide/citología , Tejido Linfoide/inmunología , Ratones , Organismos Libres de Patógenos Específicos , Regulación hacia Arriba
20.
J Immunother Cancer ; 8(1)2020 06.
Artículo en Inglés | MEDLINE | ID: mdl-32591431

RESUMEN

BACKGROUND: Tumor-infiltrating lymphocytes (TILs), mainly CD8+ cytotoxic T lymphocytes (CTL), are linked to immune-mediated control of human cancers and response to immunotherapy. Tumors have nonetheless developed specific mechanisms that selectively restrict T cell entry into the tumor microenvironment. The extracellular superoxide dismutase (SOD3) is an anti-oxidant enzyme usually downregulated in tumors. We hypothesize that upregulation of SOD3 in the tumor microenvironment might be a mechanism to boost T cell infiltration by normalizing the tumor-associated endothelium. RESULTS: Here we show that SOD3 overexpression in endothelial cells increased in vitro transmigration of naïve and activated CD4+ and CD8+ T cells, but not of myeloid cells. Perivascular expression of SOD3 also specifically increased CD4+ and CD8+ effector T cell infiltration into tumors and improved the effectiveness of adoptively transferred tumor-specific CD8+ T cells. SOD3-induced enhanced transmigration in vitro and tumor infiltration in vivo were not associated to upregulation of T cell chemokines such as CXCL9 or CXCL10, nor to changes in the levels of endothelial adhesion receptors such as intercellular adhesion molecule-1 (ICAM-1) or vascular cell adhesion molecule-1 (VCAM-1). Instead, SOD3 enhanced T cell infiltration via HIF-2α-dependent induction of specific WNT ligands in endothelial cells; this led to WNT signaling pathway activation in the endothelium, FOXM1 stabilization, and transcriptional induction of laminin-α4 (LAMA4), an endothelial basement membrane component permissive for T cell infiltration. In patients with stage II colorectal cancer, SOD3 was associated with increased CD8+ TIL density and disease-free survival. SOD3 expression was also linked to a T cell-inflamed gene signature using the COAD cohort from The Cancer Genome Atlas program. CONCLUSION: Our findings suggest that SOD3-induced upregulation of LAMA4 in endothelial cells boosts selective tumor infiltration by T lymphocytes, thus transforming immunologically "cold" into "hot" tumors. High SOD3 levels are associated with human colon cancer infiltration by CD8+ T cells, with potential consequences for the clinical outcome of these patients. Our results also uncover a cell type-specific, distinct activity of the WNT pathway for the regulation of T cell infiltration into tumors.


Asunto(s)
Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Linfocitos T CD8-positivos/inmunología , Células Endoteliales/inmunología , Linfocitos Infiltrantes de Tumor/inmunología , Neoplasias/inmunología , Superóxido Dismutasa/metabolismo , Superóxido Dismutasa/fisiología , Animales , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Femenino , Humanos , Activación de Linfocitos , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Neoplasias/metabolismo , Neoplasias/patología , Transducción de Señal , Superóxido Dismutasa/genética , Células Tumorales Cultivadas , Microambiente Tumoral
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