RESUMEN
Mammalian lymphoid immunity is mediated by fast and slow responders to pathogens. Fast innate lymphocytes are active within hours after infections in mucosal tissues. Slow adaptive lymphocytes are conventional T and B cells with clonal antigen receptors that function days after pathogen exposure. A transcription factor (TF) regulatory network guiding early T cell development is at the core of effector function diversification in all innate lymphocytes, and the kinetics of immune responses is set by developmental programming. Operational units within the innate lymphoid system are not classified by the types of pathogen-sensing machineries but rather by discrete effector functions programmed by regulatory TF networks. Based on the evolutionary history of TFs of the regulatory networks, fast effectors likely arose earlier in the evolution of animals to fortify body barriers, and in mammals they often develop in fetal ontogeny prior to the establishment of fully competent adaptive immunity.
Asunto(s)
Inmunidad Innata/fisiología , Linfocitos/inmunología , Linfocitos/metabolismo , Linfopoyesis , Factores de Transcripción/metabolismo , Animales , Evolución Biológica , Humanos , Inmunidad , Unión Proteica/inmunología , Transducción de SeñalRESUMEN
Innate lymphoid cells (ILCs) represent innate versions of T helper and cytotoxic T cells that differentiate from committed ILC precursors (ILCPs). How ILCPs give rise to mature tissue-resident ILCs remains unclear. Here, we identify circulating and tissue ILCPs in humans that fail to express the transcription factors and cytokine outputs of mature ILCs but have these signature loci in an epigenetically poised configuration. Human ILCPs robustly generate all ILC subsets in vitro and in vivo. While human ILCPs express low levels of retinoic acid receptor (RAR)-related orphan receptor C (RORC) transcripts, these cells are found in RORC-deficient patients and retain potential for EOMES+ natural killer (NK) cells, interferon gamma-positive (IFN-γ+) ILC1s, interleukin (IL)-13+ ILC2s, and for IL-22+, but not for IL-17A+ ILC3s. Our results support a model of tissue ILC differentiation ("ILC-poiesis"), whereby diverse ILC subsets are generated in situ from systemically distributed ILCPs in response to local environmental signals.
Asunto(s)
Linfocitos/citología , Células Madre/citología , Animales , Antígenos CD34/análisis , Diferenciación Celular , Linaje de la Célula , Sangre Fetal/citología , Feto/citología , Humanos , Inmunidad Innata , Interleucina-17 , Hígado/citología , Pulmón/citología , Linfocitos/inmunología , Tejido Linfoide/citología , Ratones , Proteínas Proto-Oncogénicas c-kit/análisis , Transcripción GenéticaRESUMEN
Innate lymphoid cells (ILCs) are critical effectors of innate immunity and inflammation, whose development and activation pathways make for attractive therapeutic targets. However, human ILC generation has not been systematically explored, and previous in vitro investigations relied on the analysis of few markers or cytokines, which are suboptimal to assign lineage identity. Here, we developed a platform that reliably generated human ILC lineages from CD34+ hematopoietic progenitors derived from cord blood and bone marrow. We showed that one culture condition is insufficient to generate all ILC subsets, and instead, distinct combination of cytokines and Notch signaling are essential. The identity of natural killer (NK)/ILC1s, ILC2s, and ILC3s generated in vitro was validated by protein expression, functional assays, and both global and single-cell transcriptome analysis, recapitulating the signatures and functions of their ex vivo ILC counterparts. These data represent a resource to aid in clarifying ILC biology and differentiation.
Asunto(s)
Técnicas de Cultivo de Célula/métodos , Linaje de la Célula/inmunología , Células Madre Hematopoyéticas/inmunología , Inmunidad Innata/inmunología , Linfocitos/inmunología , Antígenos CD34/inmunología , Diferenciación Celular/inmunología , Células Madre Hematopoyéticas/citología , Humanos , Linfocitos/citología , Análisis de la Célula Individual/métodosRESUMEN
Transcription factor EBF1 (early B cell factor 1) acts as a key regulator of B cell specification. The transcriptional network in which EBF1 operates has been extensively studied; however, the regulation of EBF1 function remains poorly defined. By mass spectrometric analysis of proteins associated with endogenous EBF1 in pro-B cells, we identified the nuclear import receptor Transportin-3 (Tnpo3) and found that it interacts with the immunoglobulin-like fold domain of EBF1. We delineated glutamic acid 271 of EBF1 as a critical residue for the association with Tnpo3. EBF1E271A showed normal nuclear localization; however, it had an impaired B cell programming ability in conditions of Notch signaling, as determined by retroviral transduction of Ebf1 -/- progenitors. By RNA-seq analysis of EBF1E271A-expressing progenitors, we found an up-regulation of T lineage determinants and down-regulation of early B genes, although similar chromatin binding of EBF1E271A and EBF1wt was detected in pro-B cells expressing activated Notch1. B lineage-specific inactivation of Tnpo3 in mice resulted in a block of early B cell differentiation, accompanied by a down-regulation of B lineage genes and up-regulation of T and NK lineage genes. Taken together, our observations suggest that Tnpo3 ensures B cell programming by EBF1 in nonpermissive conditions.
Asunto(s)
Ácido Glutámico , Transactivadores , beta Carioferinas , Animales , Ratones , beta Carioferinas/metabolismo , Linaje de la Célula/genética , Cromatina , Inmunoglobulinas/genética , Inmunoglobulinas/metabolismo , Carioferinas/genética , Receptores Notch/metabolismo , Transactivadores/metabolismo , Factores de Transcripción/metabolismoRESUMEN
Lymphoid tissue inducer (LTi) cells are regarded as a subset of innate lymphoid cells (ILCs). However, these cells are not derived from the ILC common progenitor, which generates other ILC subsets and is defined by the expression of the transcription factor PLZF. Here, we examined transcription factor(s) determining the fate of LTi progenitors versus non-LTi ILC progenitors. Conditional deletion of Gata3 resulted in the loss of PLZF+ non-LTi progenitors but not the LTi progenitors that expressed the transcription factor RORγt. Consistently, PLZF+ non-LTi progenitors expressed high amounts of GATA3, whereas GATA3 expression was low in RORγt+ LTi progenitors. The generation of both progenitors required the transcriptional regulator Id2, which defines the common helper-like innate lymphoid progenitor (ChILP), but not cytokine signaling. Nevertheless, low GATA3 expression was necessary for the generation of functionally mature LTi cells. Thus, differential expression of GATA3 determines the fates and functions of distinct ILC progenitors.
Asunto(s)
Factor de Transcripción GATA3/biosíntesis , Células Madre/citología , Subgrupos de Linfocitos T/citología , Linfocitos T Colaboradores-Inductores/citología , Linfocitos T Colaboradores-Inductores/inmunología , Animales , Linaje de la Célula/inmunología , Células Cultivadas , Factor de Transcripción GATA3/genética , Proteína 2 Inhibidora de la Diferenciación/metabolismo , Subunidad gamma Común de Receptores de Interleucina/genética , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/biosíntesis , Receptor de Muerte Celular Programada 1/biosíntesis , Proteína de la Leucemia Promielocítica con Dedos de Zinc/biosíntesis , Células Madre/inmunología , Subgrupos de Linfocitos T/inmunologíaRESUMEN
Aging results in increased myelopoiesis, which is linked to the increased incidence of myeloid leukemias and production of myeloid-derived suppressor cells. Here, we examined the contribution of plasma cells (PCs) to age-related increases in myelopoiesis, as PCs exhibit immune regulatory function and sequester in bone marrow (BM). PC number was increased in old BM, and they exhibited high expression of genes encoding inflammatory cytokines and pathogen sensors. Antibody-mediated depletion of PCs from old mice reduced the number of myeloid-biased hematopoietic stem cells and mature myeloid cells to levels in young animals, but lymphopoiesis was not rejuvenated, indicating that redundant mechanisms inhibit that process. PCs also regulated the production of inflammatory factors from BM stromal cells, and disruption of the PC-stromal cell circuitry with inhibitors of the cytokines IL-1 and TNF-α attenuated myelopoiesis in old mice. Thus, the age-related increase in myelopoiesis is driven by an inflammatory network orchestrated by PCs.
Asunto(s)
Envejecimiento/fisiología , Médula Ósea/fisiología , Células Madre Hematopoyéticas/patología , Inflamación/metabolismo , Mielopoyesis/fisiología , Células Plasmáticas/fisiología , Animales , Células Cultivadas , Humanos , Interleucina-1/metabolismo , Depleción Linfocítica , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
Generation of the first T lymphocytes in the human embryo involves the emergence, migration, and thymus seeding of lymphoid progenitors together with concomitant thymus organogenesis, which is the initial step to establish the entire adaptive immune system. However, the cellular and molecular programs regulating this process remain unclear. We constructed a single-cell transcriptional landscape of human early T lymphopoiesis by using cells from multiple hemogenic and hematopoietic sites spanning embryonic and fetal stages. Among heterogenous early thymic progenitors, one subtype shared common features with a subset of lymphoid progenitors in fetal liver that are known as thymus-seeding progenitors. Unbiased bioinformatics analysis identified a distinct type of pre-thymic lymphoid progenitors in the aorta-gonad-mesonephros (AGM) region. In parallel, we investigated thymic epithelial cell development and potential cell-cell interactions during thymus organogenesis. Together, our data provide insights into human early T lymphopoiesis that prospectively direct T lymphocyte regeneration, which might lead to development of clinical applications.
Asunto(s)
Diferenciación Celular/genética , Linfopoyesis/genética , Organogénesis/genética , Células Precursoras de Linfocitos T/citología , Células Precursoras de Linfocitos T/metabolismo , Timo/embriología , Biomarcadores , Diferenciación Celular/inmunología , Embrión de Mamíferos , Desarrollo Embrionario/genética , Perfilación de la Expresión Génica , Células Madre Hematopoyéticas/citología , Células Madre Hematopoyéticas/metabolismo , Humanos , Inmunofenotipificación , Linfopoyesis/inmunología , Detección de Señal Psicológica , Linfocitos T/inmunología , Linfocitos T/metabolismo , Timo/inmunología , Timo/metabolismo , TranscriptomaRESUMEN
Over the past decade our research has implemented a multimodal approach to human lymphopoiesis, combining clonal-scale mapping of lymphoid developmental architecture with the monitoring of dynamic changes in the pattern of lymphocyte generation across ontogeny. We propose that lymphopoiesis stems from founder populations of CD127/interleukin (IL)7R- or CD127/IL7R+ early lymphoid progenitors (ELPs) polarized respectively toward the T-natural killer (NK)/innate lymphoid cell (ILC) or B lineages, arising from newly characterized CD117lo multi-lymphoid progenitors (MLPs). Recent data on the lifelong lymphocyte dynamics of healthy donors suggest that, after birth, lymphopoiesis may become increasingly oriented toward the production of B lymphocytes. Stemming from this, we posit that there are three major developmental transitions, the first occurring during the neonatal period, the next at puberty, and the last during aging.
Asunto(s)
Envejecimiento , Linfopoyesis , Humanos , Envejecimiento/inmunología , Células Progenitoras Linfoides/citología , Células Progenitoras Linfoides/metabolismo , Células Progenitoras Linfoides/inmunología , Linfocitos B/inmunología , Animales , Diferenciación Celular , Células Asesinas Naturales/inmunologíaRESUMEN
The hierarchical model of hematopoiesis posits that self-renewing, multipotent hematopoietic stem cells (HSCs) give rise to all blood cell lineages. While this model accounts for hematopoiesis in transplant settings, its applicability to steady-state hematopoiesis remains to be clarified. Here, we used inducible clonal DNA barcoding of endogenous adult HSCs to trace their contribution to major hematopoietic cell lineages in unmanipulated animals. While the majority of barcodes were unique to a single lineage, we also observed frequent barcode sharing between multiple lineages, specifically between lymphocytes and myeloid cells. These results suggest that both single-lineage and multilineage contributions by HSCs collectively drive continuous hematopoiesis, and highlight a close relationship of myeloid and lymphoid development.
Asunto(s)
Células Madre Adultas , Células Madre Hematopoyéticas , Animales , Diferenciación Celular , Hematopoyesis/genética , Linaje de la Célula/genéticaRESUMEN
Traditional models of lymphopoiesis present B and T cell development as a linear process that initiates in the fetus and continues after birth in the bone marrow and thymus, respectively. However, this view of lymphocyte development is not in accord with reports, dating back several decades, indicating that the types of lymphocytes generated before and after birth differ. In this regard, selected γδ T cells, and those that utilize the Vγ3 receptor in particular, and innate-like B-1 B cells preferentially arise during fetal blood cell development. This review synthesizes data from multiple laboratories, with an emphasis on our own work using mouse models, demonstrating that innate and conventional B and T cells emerge in hematopoietic stem cell independent and dependent waves of development that are differentially regulated. This layering of lymphocyte development has implications for understanding the composition of the adult immune system and may provide insights into the origin of various lymphocytic leukemias.
Asunto(s)
Subgrupos de Linfocitos B , Linfocitos T , Humanos , Animales , Ratones , Linaje de la Célula , Células Madre Hematopoyéticas , Linfocitos , Timo , LinfopoyesisRESUMEN
Lymphoid cells encompass the adaptive immune system, including T and B cells and Natural killer T cells (NKT), and innate immune cells (ILCs), including Natural Killer (NK) cells. During adult life, these lineages are thought to derive from the differentiation of long-term hematopoietic stem cells (HSCs) residing in the bone marrow. However, during embryogenesis and fetal development, the ontogeny of lymphoid cells is both complex and multifaceted, with a large body of evidence suggesting that lymphoid lineages arise from progenitor cell populations antedating the emergence of HSCs. Recently, the application of single cell RNA-sequencing technologies and pluripotent stem cell-based developmental models has provided new insights into lymphoid ontogeny during embryogenesis. Indeed, PSC differentiation platforms have enabled de novo generation of lymphoid immune cells independently of HSCs, supporting conclusions drawn from the study of hematopoiesis in vivo. Here, we examine lymphoid development from non-HSC progenitor cells and technological advances in the differentiation of human lymphoid cells from pluripotent stem cells for clinical translation.
Asunto(s)
Células Madre Pluripotentes , Adulto , Humanos , Diferenciación Celular , Células Madre Hematopoyéticas , Células Asesinas Naturales , HematopoyesisRESUMEN
In mammals, B cells strictly segregate proliferation from somatic mutation as they develop within the bone marrow and then mature through germinal centers (GCs) in the periphery. Failure to do so risks autoimmunity and neoplastic transformation. Recent work has described how B cell progenitors transition between proliferation and mutation via cytokine signaling pathways, epigenetic chromatin regulation, and remodeling of 3D chromatin conformation. We propose a three-zone model of the GC that describes how proliferation and mutation are regulated. Using this model, we consider how recent mechanistic discoveries in B cell progenitors inform models of GC B cell function and reveal fundamental mechanisms underpinning humoral immunity, autoimmunity, and lymphomagenesis.
Asunto(s)
Linfocitos B , Centro Germinal , Humanos , Animales , Daño del ADN , Cromatina , Proliferación Celular , MamíferosRESUMEN
The classical model of hematopoiesis established in the mouse postulates that lymphoid cells originate from a founder population of common lymphoid progenitors. Here, using a modeling approach in humanized mice, we showed that human lymphoid development stemmed from distinct populations of CD127- and CD127+ early lymphoid progenitors (ELPs). Combining molecular analyses with in vitro and in vivo functional assays, we demonstrated that CD127- and CD127+ ELPs emerged independently from lympho-mono-dendritic progenitors, responded differently to Notch1 signals, underwent divergent modes of lineage restriction, and displayed both common and specific differentiation potentials. Whereas CD127- ELPs comprised precursors of T cells, marginal zone B cells, and natural killer (NK) and innate lymphoid cells (ILCs), CD127+ ELPs supported production of all NK cell, ILC, and B cell populations but lacked T potential. On the basis of these results, we propose a "two-family" model of human lymphoid development that differs from the prevailing model of hematopoiesis.
Asunto(s)
Linfocitos B/metabolismo , Células Asesinas Naturales/metabolismo , Células Progenitoras Linfoides/metabolismo , Linfopoyesis/genética , Linfocitos T/metabolismo , Adolescente , Adulto , Animales , Linfocitos B/citología , Diferenciación Celular/genética , Linaje de la Célula/genética , Células Cultivadas , Femenino , Perfilación de la Expresión Génica/métodos , Humanos , Subunidad gamma Común de Receptores de Interleucina/deficiencia , Subunidad gamma Común de Receptores de Interleucina/genética , Subunidad alfa del Receptor de Interleucina-7/genética , Subunidad alfa del Receptor de Interleucina-7/metabolismo , Células Asesinas Naturales/citología , Células Progenitoras Linfoides/citología , Células Progenitoras Linfoides/trasplante , Masculino , Ratones Endogámicos NOD , Ratones Noqueados , Ratones SCID , Persona de Mediana Edad , Trasplante de Células Madre , Linfocitos T/citología , Trasplante Heterólogo , Adulto JovenRESUMEN
Mammalian aging is associated with multiple defects of hematopoiesis, most prominently with the impaired development of T and B lymphocytes. This defect is thought to originate in hematopoietic stem cells (HSCs) of the bone marrow, specifically due to the age-dependent accumulation of HSCs with preferential megakaryocytic and/or myeloid potential ("myeloid bias"). Here, we tested this notion using inducible genetic labeling and tracing of HSCs in unmanipulated animals. We found that the endogenous HSC population in old mice shows reduced differentiation into all lineages including lymphoid, myeloid, and megakaryocytic. Single-cell RNA sequencing and immunophenotyping (CITE-Seq) showed that HSC progeny in old animals comprised balanced lineage spectrum including lymphoid progenitors. Lineage tracing using the aging-induced HSC marker Aldh1a1 confirmed the low contribution of old HSCs across all lineages. Competitive transplantations of total bone marrow cells with genetically marked HSCs revealed that the contribution of old HSCs was reduced, but compensated by other donor cells in myeloid cells but not in lymphocytes. Thus, the HSC population in old animals becomes globally decoupled from hematopoiesis, which cannot be compensated in lymphoid lineages. We propose that this partially compensated decoupling, rather than myeloid bias, is the primary cause of the selective impairment of lymphopoiesis in older mice.
Asunto(s)
Envejecimiento , Células Madre Hematopoyéticas , Ratones , Animales , Linaje de la Célula , Diferenciación Celular , Médula Ósea , Hematopoyesis , MamíferosRESUMEN
Lymphopoiesis requires the activation of lineage-specific genes embedded in naive, inaccessible chromatin or in primed, accessible chromatin. The mechanisms responsible for de novo gain of chromatin accessibility, known as "pioneer" function, remain poorly defined. Here, we showed that the EBF1 C-terminal domain (CTD) is required for the regulation of a specific gene set involved in B cell fate decision and differentiation, independently of activation and repression functions. Using genome-wide analysis of DNaseI hypersensitivity and DNA methylation in multipotent Ebf1(-/-) progenitors and derivative EBF1wt- or EBF1ΔC-expressing cells, we found that the CTD promoted chromatin accessibility and DNA demethylation in previously naive chromatin. The CTD allowed EBF1 to bind at inaccessible genomic regions that offer limited co-occupancy by other transcription factors, whereas the CTD was dispensable for EBF1 binding at regions that are occupied by multiple transcription factors. Thus, the CTD enables EBF1 to confer permissive lineage-specific changes in progenitor chromatin landscape.
Asunto(s)
Linfocitos B/fisiología , Cromatina/metabolismo , Células Progenitoras Linfoides/fisiología , Transactivadores/metabolismo , Animales , Diferenciación Celular/genética , Linaje de la Célula/genética , Células Cultivadas , Metilación de ADN/genética , Redes Reguladoras de Genes/genética , Linfopoyesis , Ratones , Ratones Noqueados , Ratones Transgénicos , Estructura Terciaria de Proteína/genética , Transactivadores/genéticaRESUMEN
B lymphocytes are crucial for the body's humoral immune response, secreting antibodies generated against foreign antigens to fight infection. Adult murine B lymphopoiesis is initiated in the bone marrow and additional maturation occurs in the spleen. In both these organs, B lymphopoiesis involves interactions with numerous different non-hematopoietic cells, also known as stromal or microenvironment cells, which provide migratory, maturation, and survival signals. A variety of conditional knockout and transgenic mouse models have been used to identify the roles of distinct microenvironment cell types in the regulation of B lymphopoiesis. These studies have revealed that mesenchymal lineage cells and endothelial cells comprise the non-hematopoietic microenvironment cell types that support B lymphopoiesis in the bone marrow. In the spleen, various types of stromal cells and endothelial cells contribute to B lymphocyte maturation. More recently, comprehensive single cell RNA-seq studies have also been used to identify clusters of stromal cell types in the bone marrow and spleen, which will aid in further identifying key regulators of B lymphopoiesis. Here, we review the different types of microenvironment cells and key extrinsic regulators that are known to be involved in the regulation of murine B lymphopoiesis in the bone marrow and spleen.
Asunto(s)
Células Endoteliales , Linfopoyesis , Animales , Linfocitos B , Médula Ósea , Células de la Médula Ósea , Ratones , Células del EstromaRESUMEN
The bone marrow has emerged as a potentially important target in cardiovascular disease as it generates all leukocytes involved in atherogenesis. In the current study, we evaluated whether a change in bone marrow functionality underlies the increased atherosclerosis susceptibility associated with high-density lipoprotein (HDL) deficiency. We found that HDL deficiency in mice due to the genetic lack of hepatocyte-derived apolipoprotein A1 (APOA1) was associated with an increase in the Lin-Sca-1+Kit+ (LSK) bone marrow stem cell population and lymphoid-primed multipotent progenitor numbers, which translated into a higher production and systemic flux of T cell subsets. In accordance with APOA1 deficiency-associated priming of stem cells to increase T lymphocyte production, atherogenic diet-fed low-density lipoprotein receptor knockout mice transplanted with bone marrow from APOA1-knockout mice displayed marked lymphocytosis as compared to wild-type bone marrow recipients. However, atherosclerotic lesion sizes and collagen contents were similar in the two groups of bone marrow recipients. In conclusion, systemic lack of APOA1 primes bone marrow stem cells for T cell lymphopoiesis. Our data provide novel evidence for a regulatory role of HDL in bone marrow functioning in normolipidemic mice.
Asunto(s)
Apolipoproteína A-I , Linfopoyesis , Animales , Apolipoproteína A-I/deficiencia , Apolipoproteína A-I/genética , Células de la Médula Ósea , Trasplante de Médula Ósea , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Receptores de LDL , Linfocitos TRESUMEN
The thymus, where T lymphocytes develop and mature, is sensitive to insults such as tissue ischemia or injury. The insults can cause thymic atrophy and compromise T-cell development, potentially impairing adaptive immunity. The objective of this study was to investigate whether myocardial infarction (MI) induces thymic injury to impair T lymphopoiesis and to uncover the underlying mechanisms. When compared with sham controls, MI mice at day 7 post-MI exhibited smaller thymus, lower cellularity, as well as less thymocytes at different developmental stages, indicative of T-lymphopoiesis impairment following MI. Accordingly, the spleen of MI mice has less T cells and recent thymic emigrants (RTEs), implying that the thymus of MI mice releases fewer mature thymocytes than sham controls. Interestingly, the secretory function of splenic T cells was not affected by MI. Further experiments showed that the reduction of thymocytes in MI mice was due to increased thymocyte apoptosis. Removal of adrenal glands by adrenalectomy (ADX) prevented MI-induced thymic injury and dysfunction, whereas corticosterone supplementation in ADX + MI mice reinduced thymic injury and dysfunction, indicating that glucocorticoids mediate thymic damage triggered by MI. Eosinophils play essential roles in thymic regeneration postirradiation, and eosinophil-deficient mice exhibit impaired thymic recovery after sublethal irradiation. Interestingly, the thymus was fully regenerated in both wild-type and eosinophil-deficient mice at day 14 post-MI, suggesting that eosinophils are not critical for thymus regeneration post-MI. In conclusion, our study demonstrates that MI-induced glucocorticoids trigger thymocyte apoptosis and impair T lymphopoiesis, resulting in less mature thymocyte release to the spleen.NEW & NOTEWORTHY The thymus is essential for maintaining whole body T-cell output. Thymic injury can adversely affect T lymphopoiesis and T-cell immune response. This study demonstrates that MI induces thymocyte apoptosis and compromises T lymphopoiesis, resulting in fewer releases of mature thymocytes to the spleen. This process is mediated by glucocorticoids secreted by adrenal glands. Therefore, targeting glucocorticoids represents a novel approach to attenuate post-MI thymic injury.
Asunto(s)
Adrenalectomía , Apoptosis , Linfopoyesis , Ratones Endogámicos C57BL , Infarto del Miocardio , Timo , Animales , Timo/patología , Timo/inmunología , Timo/efectos de los fármacos , Infarto del Miocardio/patología , Infarto del Miocardio/metabolismo , Infarto del Miocardio/inmunología , Infarto del Miocardio/fisiopatología , Masculino , Timocitos/metabolismo , Timocitos/patología , Timocitos/inmunología , Linfocitos T/inmunología , Linfocitos T/metabolismo , Glucocorticoides/farmacología , Eosinófilos/metabolismo , Eosinófilos/inmunología , Bazo/inmunología , Bazo/metabolismo , Bazo/patología , Modelos Animales de Enfermedad , Ratones , Corticosterona/sangreRESUMEN
B1 lymphocytes are a small but unique component of the innate immune-like cells. However, their ontogenic origin is still a matter of debate. Although it is widely accepted that B1 cells originate early in fetal life, whether or not they arise from hematopoietic stem cells (HSCs) is still unclear. In order to shed light on the B1 cell origin, we set out to determine whether their lineage specification is dependent on Notch signaling, which is essential for the HSC generation and, therefore, all derivatives lineages. Using mouse embryonic stem cells (mESCs) to recapitulate murine embryonic development, we have studied the requirement for Notch signaling during the earliest B-cell lymphopoiesis and found that Rbpj-deficient mESCs are able to generate B1 cells. Their Notch independence was confirmed in ex vivo experiments using Rbpj-deficient embryos. In addition, we found that upregulation of Notch signaling induced the emergence of B2 lymphoid cells. Taken together, these findings indicate that control of Notch signaling dose is crucial for different B-cell lineage specification from endothelial cells and provides pivotal information for their in vitro generation from PSCs for therapeutic applications. This article has an associated 'The people behind the papers' interview.
Asunto(s)
Subgrupos de Linfocitos B/inmunología , Desarrollo Embrionario/inmunología , Receptores Notch/inmunología , Transducción de Señal/inmunología , Animales , Diferenciación Celular/inmunología , Células Endoteliales/inmunología , Células Madre Hematopoyéticas/inmunología , Ratones , Ratones Endogámicos C57BLRESUMEN
Vaccination of farmed fish is the most effective prophylactic measure against contagious diseases but requires specific knowledge on when the adaptive immune system is fully developed. The present work describes kidney and spleen morphogenesis as well as B-cell development in the ballan wrasse (Labrus bergylta). The kidney was present at hatching (0 days pot hatching, dph) but was not lymphoid before larvae was 50-60 dph (stage 5), containing abundant Igµ+ cells. The spleen anlage was first observed in larvae at 20-30 dph and was later populated with B-cells. Unexpectedly, we found strong RAG1 signal together with abundant Igµ+ and IgM + cells in the exocrine pancreas of larvae from when the kidney was lymphoid and onwards, suggesting that B-cell lymphopoiesis occurs not only in the head kidney (HK) but also in pancreatic tissue. In this agastric fish, the pancreas is diffused along the intestine and the early presence of IgM+ B-cells in pancreatic tissue might have a role in maintain immune homeostasis in the peritoneal cavity, making a substantial contribution to early protection. IgM-secreting cells in HK indicate the presence of systemic IgM at stage 5, before the first IgM+ cells were identified in mucosal sites. This work together with our previous study on T-cell development in this species indicates that although T- and B-cells start to develop around the same time, B-cells migrate to mucosal tissues ahead of T-cells. This early migration likely involves the production of natural antibodies, contributing significantly to early protection. Moreover, a diet composed of barnacle nauplii did not result in an earlier onset of B-cell lymphopoiesis, as seen in the previous study analysing T-cell development. Nevertheless, components for adaptive immunity indicating putative immunocompetence is likely achieved in early juveniles (>100 dph). Additionally, maternal transfer of IgM to the offspring is also described. These findings provide important insights into the development of the immune system in ballan wrasse and lay the foundation for optimizing prophylactic strategies in the future. Furthermore, this work adds valuable information to broaden the knowledge on the immune system in lower vertebrates.