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1.
Immunol Rev ; 296(1): 104-119, 2020 07.
Artículo en Inglés | MEDLINE | ID: mdl-32564426

RESUMEN

Regulatory T cells (Tregs) expressing the transcription factor Foxp3 play a critical role in the control of immune homeostasis including the regulation of humoral immunity. Recently, it has become clear that a specialized subset of Tregs, T-follicular regulatory cells (Tfr), have a particular role in the control of T-follicular helper (Tfh) cell-driven germinal center (GC) responses. Following similar differentiation signals as received by Tfh, Tfr gain expression of characteristic chemokine receptors and transcription factors such as CXCR5 and BCL6 allowing them to travel to the B-cell follicle and deliver in situ suppression. It seems clear that Tfr are critical for the prevention of autoimmune antibody induction. However, their role in the control of foreign antigen-specific antibody responses appears more complex with various reports demonstrating either increased or decreased antigen-specific antibody responses following inhibition of Tfr function. Due to their recent discovery, our understanding of Tfr formation and function still has many gaps. In this review, we discuss our current knowledge of both Tregs and Tfr in the context of humoral immunity and how these cells might be manipulated in order to better control vaccine responses.


Asunto(s)
Formación de Anticuerpos/inmunología , Antígenos/metabolismo , Activación de Linfocitos/inmunología , Linfocitos T Colaboradores-Inductores/inmunología , Linfocitos T Colaboradores-Inductores/metabolismo , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/metabolismo , Animales , Biomarcadores , Epítopos/inmunología , Centro Germinal/inmunología , Centro Germinal/metabolismo , Humanos , Inmunidad Humoral , Especificidad del Receptor de Antígeno de Linfocitos T , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismo , Vacunas/inmunología
2.
Proc Natl Acad Sci U S A ; 116(2): 609-618, 2019 01 08.
Artículo en Inglés | MEDLINE | ID: mdl-30587582

RESUMEN

Anti-CTLA-4 mAb is efficacious in enhancing tumor immunity in humans. CTLA-4 is expressed by conventional T cells upon activation and by naturally occurring FOXP3+CD4+ Treg cells constitutively, raising a question of how anti-CTLA-4 mAb can differentially control these functionally opposing T cell populations in tumor immunity. Here we show that FOXP3high potently suppressive effector Treg cells were abundant in melanoma tissues, expressing CTLA-4 at higher levels than tumor-infiltrating CD8+ T cells. Upon in vitro tumor-antigen stimulation of peripheral blood mononuclear cells from healthy individuals or melanoma patients, Fc-region-modified anti-CTLA-4 mAb with high antibody-dependent cell-mediated cytotoxicity (ADCC) and cellular phagocytosis (ADCP) activity selectively depleted CTLA-4+FOXP3+ Treg cells and consequently expanded tumor-antigen-specific CD8+T cells. Importantly, the expansion occurred only when antigen stimulation was delayed several days from the antibody treatment to spare CTLA-4+ activated effector CD8+T cells from mAb-mediated killing. Similarly, in tumor-bearing mice, high-ADCC/ADCP anti-CTLA-4 mAb treatment with delayed tumor-antigen vaccination significantly prolonged their survival and markedly elevated cytokine production by tumor-infiltrating CD8+ T cells, whereas antibody treatment concurrent with vaccination did not. Anti-CTLA-4 mAb modified to exhibit a lesser or no Fc-binding activity failed to show such timing-dependent in vitro and in vivo immune enhancement. Thus, high ADCC anti-CTLA-4 mAb is able to selectively deplete effector Treg cells and evoke tumor immunity depending on the CTLA-4-expressing status of effector CD8+ T cells. These findings are instrumental in designing cancer immunotherapy with mAbs targeting the molecules commonly expressed by FOXP3+ Treg cells and tumor-reactive effector T cells.


Asunto(s)
Citotoxicidad Celular Dependiente de Anticuerpos/efectos de los fármacos , Antineoplásicos Inmunológicos/farmacología , Linfocitos T CD8-positivos/inmunología , Antígeno CTLA-4/antagonistas & inhibidores , Vacunas contra el Cáncer/farmacología , Neoplasias/inmunología , Linfocitos T Reguladores/metabolismo , Animales , Antineoplásicos Inmunológicos/inmunología , Antígeno CTLA-4/inmunología , Vacunas contra el Cáncer/inmunología , Humanos , Ratones , Ratones Endogámicos BALB C , Neoplasias/patología
3.
Nature ; 510(7505): 407-411, 2014 06 19.
Artículo en Inglés | MEDLINE | ID: mdl-24919154

RESUMEN

Inhibitors against the p110δ isoform of phosphoinositide-3-OH kinase (PI(3)K) have shown remarkable therapeutic efficacy in some human leukaemias. As p110δ is primarily expressed in leukocytes, drugs against p110δ have not been considered for the treatment of solid tumours. Here we report that p110δ inactivation in mice protects against a broad range of cancers, including non-haematological solid tumours. We demonstrate that p110δ inactivation in regulatory T cells unleashes CD8(+) cytotoxic T cells and induces tumour regression. Thus, p110δ inhibitors can break tumour-induced immune tolerance and should be considered for wider use in oncology.


Asunto(s)
Inhibidores Enzimáticos/farmacología , Tolerancia Inmunológica/efectos de los fármacos , Neoplasias/enzimología , Neoplasias/inmunología , Fosfatidilinositol 3-Quinasas/metabolismo , Linfocitos T Reguladores/efectos de los fármacos , Animales , Antineoplásicos/farmacología , Activación Enzimática/efectos de los fármacos , Tolerancia Inmunológica/inmunología , Ratones , Linfocitos T Reguladores/enzimología , Linfocitos T Reguladores/inmunología
4.
Immunology ; 157(3): 210-218, 2019 07.
Artículo en Inglés | MEDLINE | ID: mdl-31107985

RESUMEN

Tumour infiltration by regulatory T (Treg) cells contributes to suppression of the anti-tumour immune response, which limits the efficacy of immune-mediated cancer therapies. The phosphoinositide 3-kinase (PI3K) pathway has key roles in mediating the function of many immune cell subsets, including Treg cells. Treg function is context-dependent and depends on input from different cell surface receptors, many of which can activate the PI3K pathway. In this review, we explore how PI3Kδ contributes to signalling through several major immune cell receptors, including the T-cell receptor and co-stimulatory receptors such as CD28 and ICOS, but is antagonized by the immune checkpoint receptors CTLA-4 and PD-1. Understanding how PI3Kδ inhibition affects Treg signalling events will help to inform how best to use PI3Kδ inhibitors in clinical cancer treatment.


Asunto(s)
Antineoplásicos/uso terapéutico , Inmunoterapia , Linfocitos Infiltrantes de Tumor/efectos de los fármacos , Neoplasias/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Linfocitos T Reguladores/efectos de los fármacos , Animales , Antineoplásicos/efectos adversos , Fosfatidilinositol 3-Quinasa Clase Ib/inmunología , Fosfatidilinositol 3-Quinasa Clase Ib/metabolismo , Humanos , Inmunoterapia/efectos adversos , Linfocitos Infiltrantes de Tumor/enzimología , Linfocitos Infiltrantes de Tumor/inmunología , Terapia Molecular Dirigida , Neoplasias/enzimología , Neoplasias/inmunología , Neoplasias/patología , Fenotipo , Inhibidores de Proteínas Quinasas/efectos adversos , Transducción de Señal/efectos de los fármacos , Linfocitos T Reguladores/enzimología , Linfocitos T Reguladores/inmunología , Escape del Tumor , Microambiente Tumoral
6.
Blood ; 124(9): 1502-12, 2014 Aug 28.
Artículo en Inglés | MEDLINE | ID: mdl-25006123

RESUMEN

The oncomir microRNA-125b (miR-125b) is upregulated in a variety of human neoplastic blood disorders and constitutive upregulation of miR-125b in mice can promote myeloid and B-cell leukemia. We found that miR-125b promotes myeloid and B-cell neoplasm by inducing tumorigenesis in hematopoietic progenitor cells. Our study demonstrates that miR-125b induces myeloid leukemia by enhancing myeloid progenitor output from stem cells as well as inducing immortality, self-renewal, and tumorigenesis in myeloid progenitors. Through functional and genetic analyses, we demonstrated that miR-125b induces myeloid and B-cell leukemia by inhibiting interferon regulatory factor 4 (IRF4) but through distinct mechanisms; it induces myeloid leukemia through repressing IRF4 at the messenger RNA (mRNA) level without altering the genomic DNA and induces B-cell leukemia via genetic deletion of the gene encoding IRF4.


Asunto(s)
Factores Reguladores del Interferón/genética , Factores Reguladores del Interferón/metabolismo , Leucemia de Células B/genética , Leucemia de Células B/metabolismo , Leucemia Mieloide/genética , Leucemia Mieloide/metabolismo , MicroARNs/genética , MicroARNs/metabolismo , Animales , Femenino , Eliminación de Gen , Células Madre Hematopoyéticas/metabolismo , Células Madre Hematopoyéticas/patología , Humanos , Factores Reguladores del Interferón/antagonistas & inhibidores , Leucemia de Células B/etiología , Leucemia Mieloide/etiología , Ratones , Ratones Endogámicos C57BL , Trasplante de Neoplasias , Células Madre Neoplásicas/metabolismo , Células Madre Neoplásicas/patología , ARN Mensajero/genética , ARN Mensajero/metabolismo , ARN Neoplásico/genética , ARN Neoplásico/metabolismo , Regulación hacia Arriba
7.
Nucleic Acids Res ; 40(Database issue): D1047-54, 2012 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-22139925

RESUMEN

Recent advances in genome-wide association studies (GWAS) have enabled us to identify thousands of genetic variants (GVs) that are associated with human diseases. As next-generation sequencing technologies become less expensive, more GVs will be discovered in the near future. Existing databases, such as NHGRI GWAS Catalog, collect GVs with only genome-wide level significance. However, many true disease susceptibility loci have relatively moderate P values and are not included in these databases. We have developed GWASdb that contains 20 times more data than the GWAS Catalog and includes less significant GVs (P < 1.0 × 10(-3)) manually curated from the literature. In addition, GWASdb provides comprehensive functional annotations for each GV, including genomic mapping information, regulatory effects (transcription factor binding sites, microRNA target sites and splicing sites), amino acid substitutions, evolution, gene expression and disease associations. Furthermore, GWASdb classifies these GVs according to diseases using Disease-Ontology Lite and Human Phenotype Ontology. It can conduct pathway enrichment and PPI network association analysis for these diseases. GWASdb provides an intuitive, multifunctional database for biologists and clinicians to explore GVs and their functional inferences. It is freely available at http://jjwanglab.org/gwasdb and will be updated frequently.


Asunto(s)
Bases de Datos Genéticas , Enfermedad/genética , Variación Genética , Estudio de Asociación del Genoma Completo , Mapeo Cromosómico , Humanos , Anotación de Secuencia Molecular , Interfaz Usuario-Computador
8.
Sci Immunol ; 9(92): eadi9575, 2024 Feb 23.
Artículo en Inglés | MEDLINE | ID: mdl-38207015

RESUMEN

Hyperactive TLR7 signaling has long been appreciated as driver of autoimmune disease in mouse models. Recently, gain-of-function mutations in TLR7 were identified as a monogenic cause of human lupus. TLR7 is an intracellular transmembrane receptor, sensing RNA breakdown products within late endosomes. Here, we show that endosome dysfunction leads to unrestricted TLR7 signaling and is associated with human lupus. The late endosomal BORC complex together with the small GTPase Arl8b controls intracellular TLR7 levels by regulating receptor turnover. This requires a direct interaction between the TLR7-associated trafficking factor Unc93b1 and Arl8b. We identified an UNC93B1 mutation in a patient with childhood-onset lupus, which results in reduced BORC interaction and endosomal TLR7 accumulation. Therefore, a failure to control TLR7 turnover is sufficient to break immunological tolerance to nucleic acids. Our results highlight the importance of an intact endomembrane system in preventing pathological TLR7 signaling and autoimmune disease.


Asunto(s)
Enfermedades Autoinmunes , Receptor Toll-Like 7 , Ratones , Animales , Humanos , Niño , Receptor Toll-Like 7/genética , Transducción de Señal , Transporte de Proteínas , Mutación
9.
Sci Immunol ; 9(92): eadi9769, 2024 Feb 23.
Artículo en Inglés | MEDLINE | ID: mdl-38207055

RESUMEN

UNC93B1 is critical for trafficking and function of nucleic acid-sensing Toll-like receptors (TLRs) TLR3, TLR7, TLR8, and TLR9, which are essential for antiviral immunity. Overactive TLR7 signaling induced by recognition of self-nucleic acids has been implicated in systemic lupus erythematosus (SLE). Here, we report UNC93B1 variants (E92G and R336L) in four patients with early-onset SLE. Patient cells or mouse macrophages carrying the UNC93B1 variants produced high amounts of TNF-α and IL-6 and upon stimulation with TLR7/TLR8 agonist, but not with TLR3 or TLR9 agonists. E92G causes UNC93B1 protein instability and reduced interaction with TLR7, leading to selective TLR7 hyperactivation with constitutive type I IFN signaling. Thus, UNC93B1 regulates TLR subtype-specific mechanisms of ligand recognition. Our findings establish a pivotal role for UNC93B1 in TLR7-dependent autoimmunity and highlight the therapeutic potential of targeting TLR7 in SLE.


Asunto(s)
Lupus Eritematoso Sistémico , Receptor Toll-Like 7 , Ratones , Animales , Humanos , Receptor Toll-Like 7/genética , Autoinmunidad/genética , Receptor Toll-Like 9/metabolismo , Receptor Toll-Like 8 , Receptor Toll-Like 3/metabolismo , Lupus Eritematoso Sistémico/genética , Proteínas de Transporte de Membrana
10.
J Exp Med ; 220(2)2023 02 06.
Artículo en Inglés | MEDLINE | ID: mdl-36454183

RESUMEN

Thymic selection and peripheral activation of conventional T (Tconv) and regulatory T (Treg) cells depend on TCR signaling, whose anomalies are causative of autoimmunity. Here, we expressed in normal mice mutated ZAP-70 molecules with different affinities for the CD3 chains, or wild type ZAP-70 at graded expression levels under tetracycline-inducible control. Both manipulations reduced TCR signaling intensity to various extents and thereby rendered those normally deleted self-reactive thymocytes to become positively selected and form a highly autoimmune TCR repertoire. The signal reduction more profoundly affected Treg development and function because their TCR signaling was further attenuated by Foxp3 that physiologically repressed the expression of TCR-proximal signaling molecules, including ZAP-70, upon TCR stimulation. Consequently, the TCR signaling intensity reduced to a critical range generated pathogenic autoimmune Tconv cells and concurrently impaired Treg development/function, leading to spontaneous occurrence of autoimmune/inflammatory diseases, such as autoimmune arthritis and inflammatory bowel disease. These results provide a general model of how altered TCR signaling evokes autoimmune disease.


Asunto(s)
Enfermedades Autoinmunes , Animales , Ratones , Autoinmunidad , Transducción de Señal , Linfocitos T Reguladores , Receptores de Antígenos de Linfocitos T
11.
JCI Insight ; 3(11)2018 06 07.
Artículo en Inglés | MEDLINE | ID: mdl-29875319

RESUMEN

Multiple modes of immunosuppression restrain immune function within tumors. We previously reported that phosphoinositide 3-kinase δ (PI3Kδ) inactivation in mice confers resistance to a range of tumor models by disrupting immunosuppression mediated by regulatory T cells (Tregs). The PI3Kδ inhibitor idelalisib has proven highly effective in the clinical treatment of chronic lymphocytic leukemia and the potential to extend the use of PI3Kδ inhibitors to nonhematological cancers is being evaluated. In this work, we demonstrate that the antitumor effect of PI3Kδ inactivation is primarily mediated through the disruption of Treg function, and correlates with tumor dependence on Treg immunosuppression. Compared with Treg-specific PI3Kδ deletion, systemic PI3Kδ inactivation is less effective at conferring resistance to tumors. We show that PI3Kδ deficiency impairs the maturation and reduces the capacity of CD8+ cytotoxic T lymphocytes (CTLs) to kill tumor cells in vitro, and to respond to tumor antigen-specific immunization in vivo. PI3Kδ inactivation antagonized the antitumor effects of tumor vaccines and checkpoint blockade therapies intended to boost the CD8+ T cell response. These findings provide insights into mechanisms by which PI3Kδ inhibition promotes antitumor immunity and demonstrate that the mechanism is distinct from that mediated by immune checkpoint blockade.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Vacunas contra el Cáncer/farmacología , Neoplasias/tratamiento farmacológico , Inhibidores de las Quinasa Fosfoinosítidos-3 , Purinas/farmacología , Quinazolinonas/farmacología , Animales , Antígenos de Neoplasias/administración & dosificación , Antineoplásicos Inmunológicos/farmacología , Antineoplásicos Inmunológicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Vacunas contra el Cáncer/uso terapéutico , Línea Celular Tumoral/trasplante , Fosfatidilinositol 3-Quinasa Clase I , Receptores Coestimuladores e Inhibidores de Linfocitos T/antagonistas & inhibidores , Receptores Coestimuladores e Inhibidores de Linfocitos T/inmunología , Toxina Diftérica/administración & dosificación , Modelos Animales de Enfermedad , Interacciones Farmacológicas , Femenino , Humanos , Depleción Linfocítica/métodos , Masculino , Ratones , Neoplasias/inmunología , Neoplasias/patología , Fosfatidilinositol 3-Quinasas/inmunología , Fosfatidilinositol 3-Quinasas/metabolismo , Purinas/uso terapéutico , Quinazolinonas/uso terapéutico , Transducción de Señal/efectos de los fármacos , Transducción de Señal/inmunología , Linfocitos T Citotóxicos/efectos de los fármacos , Linfocitos T Citotóxicos/inmunología , Linfocitos T Reguladores/efectos de los fármacos , Linfocitos T Reguladores/inmunología , Resultado del Tratamiento
12.
JCI Insight ; 3(11)2018 06 07.
Artículo en Inglés | MEDLINE | ID: mdl-29875321

RESUMEN

Redundancy and compensation provide robustness to biological systems but may contribute to therapy resistance. Both tumor-associated macrophages (TAMs) and Foxp3+ regulatory T (Treg) cells promote tumor progression by limiting antitumor immunity. Here we show that genetic ablation of CSF1 in colorectal cancer cells reduces the influx of immunosuppressive CSF1R+ TAMs within tumors. This reduction in CSF1-dependent TAMs resulted in increased CD8+ T cell attack on tumors, but its effect on tumor growth was limited by a compensatory increase in Foxp3+ Treg cells. Similarly, disruption of Treg cell activity through their experimental ablation produced moderate effects on tumor growth and was associated with elevated numbers of CSF1R+ TAMs. Importantly, codepletion of CSF1R+ TAMs and Foxp3+ Treg cells resulted in an increased influx of CD8+ T cells, augmentation of their function, and a synergistic reduction in tumor growth. Further, inhibition of Treg cell activity either through systemic pharmacological blockade of PI3Kδ, or its genetic inactivation within Foxp3+ Treg cells, sensitized previously unresponsive solid tumors to CSF1R+ TAM depletion and enhanced the effect of CSF1R blockade. These findings identify CSF1R+ TAMs and PI3Kδ-driven Foxp3+ Treg cells as the dominant compensatory cellular components of the immunosuppressive tumor microenvironment, with implications for the design of combinatorial immunotherapies.


Asunto(s)
Resistencia a Antineoplásicos/inmunología , Depleción Linfocítica/métodos , Macrófagos/inmunología , Neoplasias/tratamiento farmacológico , Linfocitos T Reguladores/inmunología , Aminopiridinas/administración & dosificación , Animales , Línea Celular Tumoral/trasplante , Fosfatidilinositol 3-Quinasa Clase I , Toxina Diftérica/administración & dosificación , Modelos Animales de Enfermedad , Femenino , Factores de Transcripción Forkhead/metabolismo , Técnicas de Inactivación de Genes , Humanos , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Masculino , Ratones , Ratones Transgénicos , Neoplasias/inmunología , Fosfatidilinositol 3-Quinasas/genética , Fosfatidilinositol 3-Quinasas/metabolismo , Inhibidores de las Quinasa Fosfoinosítidos-3 , Cultivo Primario de Células , Purinas/administración & dosificación , Pirroles/administración & dosificación , Quinazolinonas/administración & dosificación , Receptores de Factor Estimulante de Colonias de Granulocitos y Macrófagos/metabolismo , Linfocitos T Reguladores/efectos de los fármacos , Linfocitos T Reguladores/metabolismo , Microambiente Tumoral/efectos de los fármacos , Microambiente Tumoral/inmunología
13.
Front Biosci (Landmark Ed) ; 16(5): 1634-50, 2011 01 01.
Artículo en Inglés | MEDLINE | ID: mdl-21196253

RESUMEN

There is increasing evidence that obesity may have pathophysiological effects that extend beyond its well-known co-morbidities; in particular its role in cancer has received considerable epidemiological support. As adipose tissue becomes strongly established as an endocrine organ, two of its most abundant and most investigated adipokines, leptin and adiponectin, are also taken beyond their traditional roles in energy homeostasis, and are implicated as mediators of the effects of obesity on cancer development. This review examines these adipokines in relation to the prostate, breast, colorectal, thyroid, renal, pancreatic, endometrial and oesophageal cancers, and how they may orchestrate the influence of obesity on the development of these malignancies.


Asunto(s)
Adiponectina/fisiología , Leptina/fisiología , Neoplasias/etiología , Obesidad/complicaciones , Índice de Masa Corporal , Neoplasias de la Mama/etiología , Neoplasias de la Mama/fisiopatología , Neoplasias Colorrectales/etiología , Neoplasias Colorrectales/fisiopatología , Neoplasias Endometriales/etiología , Neoplasias Endometriales/fisiopatología , Neoplasias Esofágicas/etiología , Neoplasias Esofágicas/fisiopatología , Femenino , Humanos , Neoplasias Renales/etiología , Neoplasias Renales/fisiopatología , Masculino , Neoplasias Pancreáticas/etiología , Neoplasias Pancreáticas/fisiopatología , Neoplasias de la Próstata/etiología , Neoplasias de la Próstata/fisiopatología , Neoplasias de la Tiroides/etiología , Neoplasias de la Tiroides/fisiopatología
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