RESUMEN
: Hepatitis B remains one of the major global health problems more than 40 years after the identification of human hepatitis B virus (HBV) as the causative agent. A critical turning point in combating this virus was the development of a preventative vaccine composed of the HBV surface (envelope) protein (HBsAg) to reduce the risk of new infections. The isolation of HBsAg sub-viral particles (SVPs) from the blood of asymptomatic HBV carriers as antigens for the first-generation vaccines, followed by the development of recombinant HBsAg SVPs produced in yeast as the antigenic components of the second-generation vaccines, represent landmark advancements in biotechnology and medicine. The ability of the HBsAg SVPs to accept and present foreign antigenic sequences provides the basis of a chimeric particulate delivery platform, and resulted in the development of a vaccine against malaria (RTS,S/AS01, MosquirixTM), and various preclinical vaccine candidates to overcome infectious diseases for which there are no effective vaccines. Biomedical modifications of the HBsAg subunits allowed the identification of strategies to enhance the HBsAg SVP immunogenicity to build potent vaccines for preventative and possibly therapeutic applications. The review provides an overview of the formation and assembly of the HBsAg SVPs and highlights the utilization of the particles in key effective vaccines.
Asunto(s)
Virus de la Hepatitis B/inmunología , Hepatitis B/prevención & control , Vacunas de Partículas Similares a Virus/inmunología , Vacunas contra Hepatitis Viral/inmunología , Animales , Antígenos de Superficie de la Hepatitis B/inmunología , Humanos , Ratones , Vacunas de Partículas Similares a Virus/administración & dosificación , Proteínas del Envoltorio Viral/inmunología , Vacunas contra Hepatitis Viral/clasificaciónRESUMEN
Autophagy perturbation represents an emerging therapeutic strategy in cancer. Although LATS1 and LATS2 kinases, core components of the mammalian Hippo pathway, have been shown to exert tumor suppressive activities, here we report a pro-survival role of LATS1 but not LATS2 in hepatocellular carcinoma (HCC) cells. Specifically, LATS1 restricts lethal autophagy in HCC cells induced by sorafenib, the standard of care for advanced HCC patients. Notably, autophagy regulation by LATS1 is independent of its kinase activity. Instead, LATS1 stabilizes the autophagy core-machinery component Beclin-1 by promoting K27-linked ubiquitination at lysine residues K32 and K263 on Beclin-1. Consequently, ubiquitination of Beclin-1 negatively regulates autophagy by promoting inactive dimer formation of Beclin-1. Our study highlights a functional diversity between LATS1 and LATS2, and uncovers a scaffolding role of LATS1 in mediating a cross-talk between the Hippo signaling pathway and autophagy.
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Autofagia/inmunología , Carcinoma Hepatocelular/patología , Supervivencia Celular/inmunología , Neoplasias Hepáticas/patología , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Supresoras de Tumor/metabolismo , Animales , Autofagia/efectos de los fármacos , Beclina-1/metabolismo , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/inmunología , Carcinoma Hepatocelular/mortalidad , Línea Celular Tumoral , Proliferación Celular , Supervivencia Celular/efectos de los fármacos , Conjuntos de Datos como Asunto , Supervivencia sin Enfermedad , Resistencia a Antineoplásicos/inmunología , Vía de Señalización Hippo , Humanos , Estimación de Kaplan-Meier , Hígado/patología , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/inmunología , Neoplasias Hepáticas/mortalidad , Lisina/metabolismo , Ratones , Ratones Noqueados , Organoides , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/inmunología , Estabilidad Proteica , Transducción de Señal/efectos de los fármacos , Transducción de Señal/inmunología , Sorafenib/farmacología , Sorafenib/uso terapéutico , Proteínas Supresoras de Tumor/inmunología , Ubiquitinación , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
The BCR-ABL1 fusion protein is the cause of chronic myeloid leukemia (CML) and of a significant fraction of adult-onset B cell acute lymphoblastic leukemia (B-ALL) cases. Using mouse models and patient-derived samples, we identified an essential role for γ-catenin in the initiation and maintenance of BCR-ABL1+ B-ALL but not CML. The selectivity was explained by a partial γ-catenin dependence of MYC expression together with the susceptibility of B-ALL, but not CML, to reduced MYC levels. MYC and γ-catenin enabled B-ALL maintenance by augmenting BIRC5 and enforced BIRC5 expression overcame γ-catenin loss. Since γ-catenin was dispensable for normal hematopoiesis, these lineage- and disease-specific features of canonical Wnt signaling identified a potential therapeutic target for the treatment of BCR-ABL1+ B-ALL.
Asunto(s)
Proteínas de Fusión bcr-abl/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras B/metabolismo , Vía de Señalización Wnt , gamma Catenina/metabolismo , Animales , Proteínas de Fusión bcr-abl/genética , Regulación Leucémica de la Expresión Génica , Humanos , Células K562 , Ratones Endogámicos NOD , Ratones SCID , Ratones Transgénicos , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/patología , Proteínas Proto-Oncogénicas c-myc/genética , Proteínas Proto-Oncogénicas c-myc/metabolismo , Survivin/genética , Survivin/metabolismo , beta Catenina/genética , beta Catenina/metabolismo , gamma Catenina/genéticaRESUMEN
Natural killer (NK) cells are innate cytotoxic effector cells that play important protective roles against certain pathogens as well as against pathogen-infected and transformed host cells. NK cells continuously arise from adult bone marrow-resident haematopoietic progenitors. Their generation can be sub-divided into three phases. The early NK cell development phase from multipotent common lymphoid progenitors occurs at least in part in common with that of additional members of a family of innate lymphoid cells, for which NK cells are the founding member. An intermediate phase of NK cell differentiation is characterized by the acquisition of IL-15 responsiveness and lineage-defining properties such as the transcription of genes coding for cytotoxic effector molecules. This is followed by a late maturation phase during which NK cells lose homeostatic expansion and increase effector capacity. These three phases are regulated by multiple stage-specific but not NK cell-specific transcription factors. This review summarizes the NK cell developmental and maturation processes and their transcriptional regulation with an emphasis on data derived from genetically modified mouse models.
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Diferenciación Celular , Regulación de la Expresión Génica , Células Asesinas Naturales/citología , Células Asesinas Naturales/metabolismo , Animales , Antígeno CD11b/metabolismo , Citocinas/metabolismo , Linfocitos/citología , Linfocitos/metabolismo , Factores de Transcripción/metabolismo , Miembro 7 de la Superfamilia de Receptores de Factores de Necrosis Tumoral/metabolismoRESUMEN
The transcription factor Tcf1 is essential for the development of natural killer (NK) cells. However, its precise role has not been clarified. Our combined analysis of Tcf1-deficient and transgenic mice indicated that Tcf1 guides NK cells through three stages of development. Tcf1 expression directed bone marrow progenitors toward the NK cell lineage and ensured the survival of NK-committed cells, and its downregulation was needed for terminal maturation. Impaired survival of NK-committed cells was due to excessive expression of granzyme B (GzmB) and other granzyme family members, which induced NK cell self-destruction during maturation and following activation with cytokines or target cells. Mechanistically, Tcf1 binding reduced the activity of a Gzmb-associated regulatory element, and this accounted for the reduced Gzmb expression in Tcf1-expressing NK cells. These data identify an unexpected requirement to limit the expression of cytotoxic effector molecules for the normal expansion and function of NK cells.
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Regulación Enzimológica de la Expresión Génica/inmunología , Granzimas/inmunología , Factor Nuclear 1-alfa del Hepatocito/inmunología , Células Asesinas Naturales/inmunología , Animales , Granzimas/genética , Factor Nuclear 1-alfa del Hepatocito/genética , Ratones , Ratones NoqueadosRESUMEN
Natural Killer (NK) cells attack normal hematopoietic cells that do not express inhibitory MHC class I (MHC-I) molecules, but the ligands that activate NK cells remain incompletely defined. Here we show that the expression of the Signaling Lymphocyte Activation Molecule (SLAM) family members CD48 and Ly9 (CD229) by MHC-I-deficient tumor cells significantly contributes to NK cell activation. When NK cells develop in the presence of T cells or B cells that lack inhibitory MHC-I but express activating CD48 and Ly9 ligands, the NK cells' ability to respond to MHC-I-deficient tumor cells is severely compromised. In this situation, NK cells express normal levels of the corresponding activation receptors 2B4 (CD244) and Ly9 but these receptors are non-functional. This provides a partial explanation for the tolerance of NK cells to MHC-I-deficient cells in vivo. Activating signaling via 2B4 is restored when MHC-I-deficient T cells are removed, indicating that interactions with MHC-I-deficient T cells dominantly, but not permanently, impair the function of the 2B4 NK cell activation receptor. These data identify an important role of SLAM family receptors for NK cell mediated "missing-self" reactivity and suggest that NK cell tolerance in MHC-I mosaic mice is in part explained by an acquired dysfunction of SLAM family receptors.
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Antígenos CD/metabolismo , Antígenos de Histocompatibilidad Clase I/metabolismo , Células Asesinas Naturales/inmunología , Melanoma Experimental/inmunología , Receptores de Superficie Celular/metabolismo , Autotolerancia/inmunología , Animales , Antígenos CD/inmunología , Citometría de Flujo , Antígenos de Histocompatibilidad Clase I/inmunología , Melanoma Experimental/patología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Receptores de Superficie Celular/inmunología , Receptores Inmunológicos/metabolismo , Familia de Moléculas Señalizadoras de la Activación Linfocitaria , Miembro 1 de la Familia de Moléculas Señalizadoras de la Activación Linfocitaria , Células Tumorales CultivadasRESUMEN
Natural Killer (NK) cells use germ line encoded receptors to detect diseased host cells. Despite the invariant recognition structures, NK cells have a significant ability to adapt to their surroundings, such as the presence or absence of MHC class I molecules. It has been assumed that this adaptation occurs during NK cell development, but recent findings show that mature NK cells can also adapt to the presence or absence of MHC class I molecules. Here, we summarize how NK cells adjust to changes in the expression of MHC class I molecules. We propose an extension of existing models, in which MHC class I recognition during NK cell development sequentially instructs and maintains NK cell function. The elucidation of the molecular basis of the two effects may identify ways to improve the fitness of NK cells and to prevent the loss of NK cell function due to persistent alterations in their environment.
RESUMEN
Protection against reinfection is mediated by Ag-specific memory CD8 T cells, which display stem cell-like function. Because canonical Wnt (Wingless/Int1) signals critically regulate renewal versus differentiation of adult stem cells, we evaluated Wnt signal transduction in CD8 T cells during an immune response to acute infection with lymphocytic choriomeningitis virus. Whereas naive CD8 T cells efficiently transduced Wnt signals, at the peak of the primary response to infection only a fraction of effector T cells retained signal transduction and the majority displayed strongly reduced Wnt activity. Reduced Wnt signaling was in part due to the downregulation of Tcf-1, one of the nuclear effectors of the pathway, and coincided with progress toward terminal differentiation. However, the correlation between low and high Wnt levels with short-lived and memory precursor effector cells, respectively, was incomplete. Adoptive transfer studies showed that low and high Wnt signaling did not influence cell survival but that Wnt high effectors yielded memory cells with enhanced proliferative potential and stronger protective capacity. Likewise, following adoptive transfer and rechallenge, memory cells with high Wnt levels displayed increased recall expansion, compared with memory cells with low Wnt signaling, which were preferentially effector-like memory cells, including tissue-resident memory cells. Thus, canonical Wnt signaling identifies CD8 T cells with enhanced proliferative potential in part independent of commonly used cell surface markers to discriminate effector and memory T cell subpopulations. Interventions that maintain Wnt signaling may thus improve the formation of functional CD8 T cell memory during vaccination.
Asunto(s)
Linfocitos T CD8-positivos/inmunología , Coriomeningitis Linfocítica/inmunología , Virus de la Coriomeningitis Linfocítica/inmunología , Proteínas Wnt/inmunología , Vía de Señalización Wnt/inmunología , Traslado Adoptivo , Animales , Proteína Axina/biosíntesis , Linfocitos T CD8-positivos/trasplante , Diferenciación Celular/inmunología , Proliferación Celular , Regulación hacia Abajo , Factor Nuclear 1-alfa del Hepatocito/biosíntesis , Memoria Inmunológica/inmunología , Lectinas Tipo C , Coriomeningitis Linfocítica/virología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Receptores Inmunológicos/biosíntesis , Subgrupos de Linfocitos T/inmunología , VacunaciónRESUMEN
Natural killer (NK) cells are capable of directly recognizing pathogens, pathogen-infected cells, and transformed cells. NK cells recognize target cells using approximately 100 germ-line encoded receptors, which display activating or inhibitory function. NK cell activation usually requires the engagement of more than one receptor, and these may contribute distinct signaling inputs that are required for the firm adhesion of NK cells to target cells, polarization, and the release of cytotoxic granules, as well as the production of cytokines. In this article we discuss receptor-mediated mechanisms that counteract NK cell activation. The distinct intracellular inhibitory signaling pathways and how they can dominantly interfere with NK cell activation signaling events are discussed first. In addition, mechanisms by which inhibitory receptors modulate cellular activation at the level of receptor-ligand interactions are described. Receptor-mediated inhibition of NK cell function serves three main purposes: ensuring tolerance of NK cells to normal cells, enabling NK cell responses to aberrant host cells that have lost an inhibitory ligand, and, finally, allowing the recognition of certain pathogens that do not express inhibitory ligands.
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Regulación de la Expresión Génica/inmunología , Células Asesinas Naturales/inmunología , Receptor Cross-Talk/inmunología , Receptores KIR/inmunología , Animales , Adhesión Celular , Citocinas/genética , Citocinas/inmunología , Gránulos Citoplasmáticos/inmunología , Gránulos Citoplasmáticos/metabolismo , Antígenos de Histocompatibilidad Clase I/genética , Antígenos de Histocompatibilidad Clase I/inmunología , Humanos , Tolerancia Inmunológica , Células Asesinas Naturales/citología , Ligandos , Activación de Linfocitos , Receptores KIR/genética , Transducción de SeñalRESUMEN
Immunoglobulin class switch recombination (CSR) is initiated by double-stranded DNA breaks (DSBs) in switch regions triggered by activation-induced cytidine deaminase (AID). Although CSR correlates with epigenetic modifications at the IgH locus, the relationship between these modifications and AID remains unknown. In this study, we show that during CSR, AID forms a complex with KAP1 (KRAB domain-associated protein 1) and HP1 (heterochromatin protein 1) that is tethered to the donor switch region (Sµ) bearing H3K9me3 (trimethylated histone H3 at lysine 9) in vivo. Furthermore, in vivo disruption of this complex results in impaired AID recruitment to Sµ, inefficient DSB formation, and a concomitant defect in CSR but not in somatic hypermutation. We propose that KAP1 and HP1 tether AID to H3K9me3 residues at the donor switch region, thus providing a mechanism linking AID to epigenetic modifications during CSR.