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2.
Methods Mol Biol ; 2580: 211-232, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-36374460

RESUMEN

T cells and innate lymphoid cells (ILCs) share expression of many key transcription factors during development and at mature stage, resulting in striking functional similarities between these lineages. Taking into account ILC contribution is thus necessary to appreciate T cell functions during immune responses. Furthermore, understanding ILC development and functions helps to understand T cells. Here we provide methods and protocols to isolate pure populations of multipotent precursors to T cells and innate lymphoid cells (ILCs) from adult mouse bone marrow, using flow cytometric sorting. These include precursors to all lymphocytes (viz., LMPPs and ALPs) and multipotent precursors to ILCs that have been recently refined (viz., specified EILPs, committed EILPs, and ILCPs).


Asunto(s)
Linfocitos , Linfocitos T , Ratones , Animales , Inmunidad Innata , Médula Ósea , Células Progenitoras Linfoides/metabolismo , Diferenciación Celular
3.
Cell Rep ; 41(5): 111569, 2022 11 01.
Artículo en Inglés | MEDLINE | ID: mdl-36323259

RESUMEN

Innate lymphoid cells (ILCs) play important roles in regulating tissue homeostasis and innate immune responses. Generation of ILCs after engraftment of pluripotent stem cell (PSC)-derived hematopoietic progenitors (iHPCs) has not yet been reported. Here, we document that ILCs exist in Rag2-/-Il2rg-/- recipients engrafted with PSC-derived iHPCs guided by Runx1 and Hoxa9 expression. Upon transplantation, iHPCs immediately give rise to ILC-related progenitors containing common helper ILC progenitors in the bone marrow, followed by a more restricted population named ILC progenitors, which are able to further differentiate into mature ILCs in the primary and secondary immunodeficient recipients. The PSC-derived ILCs exhibit multiple tissue distributions and normal immunological functions. Single-cell transcriptomics illustrates the developmental trajectory of PSC-derived ILCs in vivo, which is consistent with that of natural ILCs. Our study provides insights into the generation of ILCs in animals transplanted with PSC-derived iHPCs as a cell source.


Asunto(s)
Inmunidad Innata , Células Madre Pluripotentes , Animales , Linfocitos/metabolismo , Diferenciación Celular , Células Progenitoras Linfoides/metabolismo
4.
Front Immunol ; 13: 957711, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-36268032

RESUMEN

Innate lymphoid cells (ILCs) harbor tissue-resident properties in border zones, such as the mucosal membranes and the skin. ILCs exert a wide range of biological functions, including inflammatory response, maintenance of tissue homeostasis, and metabolism. Since its discovery, tremendous effort has been made to clarify the nature of ILCs, and scientific progress revealed that progenitor cells of ILC can produce ILC subsets that are functionally reminiscent of T-cell subsets such as Th1, Th2, and Th17. Thus, now it comes to the notion that ILC progenitors are considered an innate version of naïve T cells. Another important discovery was that ILC progenitors in the different tissues undergo different modes of differentiation pathways. Furthermore, during the embryonic phase, progenitor cells in different developmental chronologies give rise to the unique spectra of immune cells and cause a wave to replenish the immune cells in tissues. This observation leads to the concept of layered immunity, which explains the ontology of some cell populations, such as B-1a cells, γδ T cells, and tissue-resident macrophages. Thus, recent reports in ILC biology posed a possibility that the concept of layered immunity might disentangle the complexity of ILC heterogeneity. In this review, we compare ILC ontogeny in the bone marrow with those of embryonic tissues, such as the fetal liver and embryonic thymus, to disentangle ILC heterogeneity in light of layered immunity.


Asunto(s)
Inmunidad Innata , Linfocitos , Células Progenitoras Linfoides , Diferenciación Celular , Linfocitos B
5.
J Biol Chem ; 298(11): 102506, 2022 11.
Artículo en Inglés | MEDLINE | ID: mdl-36126774

RESUMEN

Hematopoietic stem and progenitor cells can differentiate into all types of blood cells. Regulatory mechanisms underlying pluripotency in progenitors, such as the ability of lymphoid progenitor cells to differentiate into T-lineage, remain unclear. We have previously reported that LIM domain only 2 (Lmo2), a bridging factor in large transcriptional complexes, is essential to retain the ability of lymphoid progenitors to differentiate into T-lineage. However, biochemical characterization of Lmo2 protein complexes in physiological hematopoietic progenitors remains obscure. Here, we identified approximately 600 Lmo2-interacting molecules in a lymphoid progenitor cell line by two-step affinity purification with LC-MS/MS analysis. Zinc finger and BTB domain containing 1 (Zbtb1) and CBFA2/RUNX1 partner transcriptional corepressor 3 (Cbfa2t3) were found to be the functionally important binding partners of Lmo2. We determined CRISPR/Cas9-mediated acute disruption of Zbtb1 or Cbfa2t3 in the lymphoid progenitor or bone marrow-derived primary hematopoietic progenitor cells causes significant defects in the initiation of T-cell development when Notch signaling is activated. Our transcriptome analysis of Zbtb1- or Cbfa2t3-deficient lymphoid progenitors revealed that Tcf7 was a common target for both factors. Additionally, ChIP-seq analysis showed that Lmo2, Zbtb1, and Cbfa2t3 cobind to the Tcf7 upstream enhancer region, which is occupied by the Notch intracellular domain/RBPJ transcriptional complex after Notch stimulation, in lymphoid progenitors. Moreover, transduction with Tcf7 restored the defect in the T-lineage potential of Zbtb1-deficient lymphoid progenitors. Thus, in lymphoid progenitors, the Lmo2/Zbtb1/Cbfa2t3 complex directly binds to the Tcf7 locus and maintains responsiveness to the Notch-mediated inductive signaling to facilitate T-lineage differentiation.


Asunto(s)
Células Progenitoras Linfoides , Factores de Transcripción , Células Progenitoras Linfoides/fisiología , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Cromatografía Liquida , Espectrometría de Masas en Tándem , Células Madre Hematopoyéticas/metabolismo , Diferenciación Celular , Proteínas con Dominio LIM/genética , Proteínas con Dominio LIM/metabolismo
6.
STAR Protoc ; 3(3): 101534, 2022 09 16.
Artículo en Inglés | MEDLINE | ID: mdl-35830307

RESUMEN

Innate lymphoid cells (ILCs) and adaptive T cells remain a challenge to study because of a significant overlap in their transcriptomic profiles. Here, we describe the adoptive transfer of ILC progenitors into mice genetically deficient in innate and adaptive immune cells to allow detailed study of the development and function of ILCs and gene regulation in an in vivo setting. For complete details on the use and execution of this protocol, please refer to Jacquelot et al. (2021) and Seillet et al. (2016).


Asunto(s)
Inmunidad Innata , Linfocitos , Animales , Médula Ósea , Células Progenitoras Linfoides , Ratones , Linfocitos T
7.
Nat Commun ; 13(1): 4344, 2022 07 27.
Artículo en Inglés | MEDLINE | ID: mdl-35896601

RESUMEN

Innate lymphoid cells (ILCs) include cytotoxic natural killer cells and distinct groups of cytokine-producing innate helper cells which participate in immune defense and promote tissue homeostasis. Circulating human ILC precursors (ILCP) able to generate all canonical ILC subsets via multi-potent or uni-potent intermediates according to our previous work. Here we show potential cooperative roles for the Notch and IL-23 signaling pathways for human ILC differentiation from blood ILCP using single cell cloning analyses and validate these findings in patient samples with rare genetic deficiencies in IL12RB1 and RORC. Mechanistically, Notch signaling promotes upregulation of the transcription factor RORC, enabling acquisition of Group 1 (IFN-γ) and Group 3 (IL-17A, IL-22) effector functions in multi-potent and uni-potent ILCP. Interfering with RORC or signaling through its target IL-23R compromises ILC3 effector functions but also generally suppresses ILC production from multi-potent ILCP. Our results identify a Notch->RORC- > IL-23R pathway which operates during human ILC differentiation. These observations may help guide protocols to expand functional ILC subsets in vitro with an aim towards novel ILC therapies for human disease.


Asunto(s)
Inmunidad Innata , Linfocitos , Diferenciación Celular , Humanos , Interleucina-23 , Células Asesinas Naturales , Células Progenitoras Linfoides/fisiología , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/genética , Receptores Notch/metabolismo
8.
Front Immunol ; 13: 854312, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35757763

RESUMEN

Natural killer (NK) cells play roles in viral clearance and early surveillance against malignant transformation, yet our knowledge of the underlying mechanisms controlling their development and functions remain incomplete. To reveal cell fate-determining pathways in NK cell progenitors (NKP), we utilized an unbiased approach and generated comprehensive gene expression profiles of NK cell progenitors. We found that the NK cell program was gradually established in the CLP to preNKP and preNKP to rNKP transitions. In line with FOXO1 and FOXO3 being co-expressed through the NK developmental trajectory, the loss of both perturbed the establishment of the NK cell program and caused stalling in both NK cell development and maturation. In addition, we found that the combined loss of FOXO1 and FOXO3 caused specific changes to the composition of the non-cytotoxic innate lymphoid cell (ILC) subsets in bone marrow, spleen, and thymus. By combining transcriptome and chromatin profiling, we revealed that FOXO TFs ensure proper NK cell development at various lineage-commitment stages through orchestrating distinct molecular mechanisms. Combined FOXO1 and FOXO3 deficiency in common and innate lymphoid cell progenitors resulted in reduced expression of genes associated with NK cell development including ETS-1 and their downstream target genes. Lastly, we found that FOXO1 and FOXO3 controlled the survival of committed NK cells via gene regulation of IL-15Rß (CD122) on rNKPs and bone marrow NK cells. Overall, we revealed that FOXO1 and FOXO3 function in a coordinated manner to regulate essential developmental genes at multiple stages during murine NK cell and ILC lineage commitment.


Asunto(s)
Proteína Forkhead Box O1 , Proteína Forkhead Box O3 , Células Asesinas Naturales , Células Progenitoras Linfoides , Animales , Diferenciación Celular/inmunología , Proteína Forkhead Box O1/inmunología , Proteína Forkhead Box O3/inmunología , Inmunidad Innata , Células Asesinas Naturales/citología , Células Asesinas Naturales/inmunología , Células Progenitoras Linfoides/citología , Células Progenitoras Linfoides/inmunología , Ratones , Ratones Endogámicos C57BL
9.
Front Immunol ; 13: 880668, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35603175

RESUMEN

The development of B cells relies on an intricate network of transcription factors critical for developmental progression and lineage commitment. In the B cell developmental trajectory, a temporal switch from predominant Foxo3 to Foxo1 expression occurs at the CLP stage. Utilizing VAV-iCre mediated conditional deletion, we found that the loss of FOXO3 impaired B cell development from LMPP down to B cell precursors, while the loss of FOXO1 impaired B cell commitment and resulted in a complete developmental block at the CD25 negative proB cell stage. Strikingly, the combined loss of FOXO1 and FOXO3 resulted in the failure to restrict the myeloid potential of CLPs and the complete loss of the B cell lineage. This is underpinned by the failure to enforce the early B-lineage gene regulatory circuitry upon a predominantly pre-established open chromatin landscape. Altogether, this demonstrates that FOXO3 and FOXO1 cooperatively govern early lineage restriction and initiation of B-lineage commitment in CLPs.


Asunto(s)
Hematopoyesis , Células Progenitoras Linfoides , Linfocitos B/metabolismo , Proteína Forkhead Box O1/genética , Proteína Forkhead Box O1/metabolismo , Hematopoyesis/genética , Células Progenitoras Linfoides/metabolismo , Células Precursoras de Linfocitos B/metabolismo
10.
J Immunol ; 208(5): 1066-1075, 2022 03 01.
Artículo en Inglés | MEDLINE | ID: mdl-35140132

RESUMEN

BATF3-deficient mice that lack CD8+ dendritic cells (DCs) showed an exacerbation of chronic graft-versus-host disease (cGVHD), including T follicular helper (Tfh) cell and autoantibody responses, whereas mice carrying the Sle2c2 lupus-suppressive locus with a mutation in the G-CSFR showed an expansion of CD8+ DCs and a poor mobilization of plasmacytoid DCs (pDCs) and responded poorly to cGVHD induction. Here, we investigated the contribution of CD8+ DCs and pDCs to the humoral response to protein immunization, where CD8neg DCs are thought to represent the major inducers. Both BATF3-/- and Sle2c2 mice had reduced humoral and germinal center (GC) responses compared with C57BL/6 (B6) controls. We showed that B6-derived CD4+ DCs are the major early producers of IL-6, followed by CD4-CD8- DCs. Surprisingly, IL-6 production and CD80 expression also increased in CD8+ DCs after immunization, and B6-derived CD8+ DCs rescued Ag-specific adaptive responses in BATF3-/- mice. In addition, inflammatory pDCs (ipDCs) produced more IL-6 than all conventional DCs combined. Interestingly, G-CSFR is highly expressed on pDCs. G-CSF expanded pDC and CD8+ DC numbers and IL-6 production by ipDCs and CD4+ DCs, and it improved the quality of Ab response, increasing the localization of Ag-specific T cells to the GC. Finally, G-CSF activated STAT3 in early G-CSFR+ common lymphoid progenitors of cDCs/pDCs but not in mature cells. In conclusion, we showed a multilayered role of DC subsets in priming Tfh cells in protein immunization, and we unveiled the importance of G-CSFR signaling in the development and function pDCs.


Asunto(s)
Células Dendríticas/inmunología , Enfermedad Injerto contra Huésped/inmunología , Células Progenitoras Linfoides/citología , Receptores de Factor Estimulante de Colonias de Granulocito/metabolismo , Células T Auxiliares Foliculares/inmunología , Traslado Adoptivo , Animales , Autoanticuerpos/inmunología , Antígeno B7-1/biosíntesis , Factores de Transcripción con Cremalleras de Leucina de Carácter Básico/genética , Antígenos CD4/biosíntesis , Antígenos CD8/biosíntesis , Diferenciación Celular/inmunología , Células Dendríticas/trasplante , Femenino , Factor Estimulante de Colonias de Granulocitos/metabolismo , Interleucina-6/biosíntesis , Activación de Linfocitos/inmunología , Células Progenitoras Linfoides/inmunología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Receptores de Factor Estimulante de Colonias de Granulocito/genética , Proteínas Represoras/genética , Factor de Transcripción STAT3/metabolismo , Transducción de Señal/inmunología
11.
Int J Mol Sci ; 23(3)2022 Jan 20.
Artículo en Inglés | MEDLINE | ID: mdl-35163045

RESUMEN

Understanding the emergence of lymphoid committed cells from multipotent progenitors (MPP) is a great challenge in hematopoiesis. To gain deeper insight into the dynamic expression changes associated with these transitions, we report the quantitative transcriptome of two MPP subsets and the common lymphoid progenitor (CLP). While the transcriptome is rather stable between MPP2 and MPP3, expression changes increase with differentiation. Among those, we found that pioneer lymphoid genes such as Rag1, Mpeg1, and Dntt are expressed continuously from MPP2. Others, such as CD93, are CLP specific, suggesting their potential use as new markers to improve purification of lymphoid populations. Notably, a six-transcription factor network orchestrates the lymphoid differentiation program. Additionally, we pinpointed 24 long intergenic-non-coding RNA (lincRNA) differentially expressed through commitment and further identified seven novel forms. Collectively, our approach provides a comprehensive landscape of coding and non-coding transcriptomes expressed during lymphoid commitment.


Asunto(s)
Perfilación de la Expresión Génica/métodos , Redes Reguladoras de Genes , Hematopoyesis , Células Progenitoras Linfoides/citología , ARN Largo no Codificante/genética , Animales , Células Cultivadas , Femenino , Regulación de la Expresión Génica , Marcadores Genéticos , Secuenciación de Nucleótidos de Alto Rendimiento , Células Progenitoras Linfoides/química , Masculino , Ratones , Análisis de Secuencia de ARN
12.
Cell Rep ; 38(3): 110266, 2022 01 18.
Artículo en Inglés | MEDLINE | ID: mdl-35045305

RESUMEN

Production of effector CD8+ T cells during persistent infection requires a stable pool of stem-like cells that can give rise to effector cells via a proliferative intermediate population. In infection models marked by T cell exhaustion, this process can be transiently induced by checkpoint blockade but occurs spontaneously in mice chronically infected with the protozoan intracellular parasite Toxoplasma gondii. We observe distinct locations for parasite-specific T cell subsets, implying a link between differentiation and anatomical niches in the spleen. Loss of the chemokine receptor CXCR3 on T cells does not prevent white pulp-to-red pulp migration but reduces interactions with CXCR3 ligand-producing dendritic cells (DCs) and impairs memory-to-intermediate transition, leading to a buildup of memory T cells in the red pulp. Thus, CXCR3 increases T cell exposure to differentiation-inducing signals during red pulp migration, providing a dynamic mechanism for modulating effector differentiation in response to environmental signals.


Asunto(s)
Linfocitos T CD8-positivos/inmunología , Diferenciación Celular/inmunología , Células Dendríticas/inmunología , Células Progenitoras Linfoides/inmunología , Receptores CXCR3/inmunología , Bazo/inmunología , Animales , Ratones , Infección Persistente/inmunología , Toxoplasmosis Animal/inmunología
13.
J Exp Med ; 219(3)2022 03 07.
Artículo en Inglés | MEDLINE | ID: mdl-34928315

RESUMEN

In the mouse, the first hematopoietic cells are generated in the yolk sac from the primitive, erythro-myeloid progenitor (EMP) and lymphoid programs that are specified before the emergence of hematopoietic stem cells. While many of the yolk sac-derived populations are transient, specific immune cell progeny seed developing tissues, where they function into adult life. To access the human equivalent of these lineages, we modeled yolk sac hematopoietic development using pluripotent stem cell differentiation. Here, we show that the combination of Activin A, BMP4, and FGF2 induces a population of KDR+CD235a/b+ mesoderm that gives rise to the spectrum of erythroid, myeloid, and T lymphoid lineages characteristic of the mouse yolk sac hematopoietic programs, including the Vδ2+ subset of γ/δ T cells that develops early in the human embryo. Through clonal analyses, we identified a multipotent hematopoietic progenitor with erythroid, myeloid, and T lymphoid potential, suggesting that the yolk sac EMP and lymphoid lineages may develop from a common progenitor.


Asunto(s)
Hematopoyesis , Modelos Biológicos , Células Madre Pluripotentes/citología , Células Madre Pluripotentes/metabolismo , Saco Vitelino/citología , Animales , Biomarcadores , Diferenciación Celular/genética , Hematopoyesis/fisiología , Células Madre Hematopoyéticas/citología , Células Madre Hematopoyéticas/metabolismo , Humanos , Inmunofenotipificación , Células Progenitoras Linfoides/citología , Células Progenitoras Linfoides/metabolismo , Linfopoyesis/genética , Ratones , Receptores de Antígenos de Linfocitos T/genética , Receptores de Antígenos de Linfocitos T/metabolismo
14.
J Exp Med ; 219(2)2022 02 07.
Artículo en Inglés | MEDLINE | ID: mdl-34958351

RESUMEN

During dendritic cell (DC) development, Myc expression in progenitors is replaced by Mycl in mature DCs, but when and how this transition occurs is unknown. We evaluated DC development using reporters for MYC, MYCL, and cell cycle proteins Geminin and CDT1 in wild-type and various mutant mice. For classical type 1 dendritic cells (cDC1s) and plasmacytoid DCs (pDCs), the transition occurred upon their initial specification from common dendritic cell progenitors (CDPs) or common lymphoid progenitors (CLPs), respectively. This transition required high levels of IRF8 and interaction with PU.1, suggesting the use of EICEs within Mycl enhancers. In pDCs, maximal MYCL induction also required the +41kb Irf8 enhancer that controls pDC IRF8 expression. IRF8 also contributed to repression of MYC. While MYC is expressed only in rapidly dividing DC progenitors, MYCL is most highly expressed in DCs that have exited the cell cycle. Thus, IRF8 levels coordinate the Myc-Mycl transition during DC development.


Asunto(s)
Diferenciación Celular/genética , Células Dendríticas/citología , Células Dendríticas/metabolismo , Regulación de la Expresión Génica , Genes myc , Factores Reguladores del Interferón/genética , Animales , Proteínas de Ciclo Celular/genética , Elementos de Facilitación Genéticos , Genes Reporteros , Inmunofenotipificación , Factores Reguladores del Interferón/metabolismo , Células Progenitoras Linfoides/citología , Células Progenitoras Linfoides/inmunología , Células Progenitoras Linfoides/metabolismo , Ratones , Ratones Noqueados , Unión Proteica , Proteínas Proto-Oncogénicas/metabolismo , Transactivadores/metabolismo
15.
Front Immunol ; 12: 791220, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34917097

RESUMEN

T cell factor 1 (Tcf1) is known as a critical mediator for natural killer (NK) cell development and terminal maturation. However, its essential targets and precise mechanisms involved in early NK progenitors (NKP) are not well clarified. To investigate the role of Tcf1 in NK cells at distinct developmental phases, we employed three kinds of genetic mouse models, namely, Tcf7fl/flVavCre/+, Tcf7fl/flCD122Cre/+ and Tcf7fl/flNcr1Cre/+ mice, respectively. Similar to Tcf1 germline knockout mice, we found notably diminished cell number and defective development in BM NK cells from all strains. In contrast, Tcf7fl/flNcr1Cre/+ mice exhibited modest defects in splenic NK cells compared with those in the other two strains. By analyzing the published ATAC-seq and ChIP-seq data, we found that Tcf1 directly targeted 110 NK cell-related genes which displayed differential accessibility in the absence of Tcf1. Along with this clue, we further confirmed that a series of essential regulators were expressed aberrantly in distinct BM NK subsets with conditional ablating Tcf1 at NKP stage. Eomes, Ets1, Gata3, Ikzf1, Ikzf2, Nfil3, Runx3, Sh2d1a, Slamf6, Tbx21, Tox, and Zeb2 were downregulated, whereas Spi1 and Gzmb were upregulated in distinct NK subsets due to Tcf1 deficiency. The dysregulation of these genes jointly caused severe defects in NK cells lacking Tcf1. Thus, our study identified essential targets of Tcf1 in NK cells, providing new insights into Tcf1-dependent regulatory programs in step-wise governing NK cell development.


Asunto(s)
Factor Nuclear 1-alfa del Hepatocito/metabolismo , Células Asesinas Naturales/fisiología , Subgrupos Linfocitarios/fisiología , Células Progenitoras Linfoides/fisiología , Animales , Antígenos Ly/genética , Antígenos Ly/metabolismo , Diferenciación Celular , Células Cultivadas , Regulación de la Expresión Génica , Granzimas/genética , Granzimas/metabolismo , Factor Nuclear 1-alfa del Hepatocito/genética , Activación de Linfocitos , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Receptor 1 Gatillante de la Citotoxidad Natural/genética , Receptor 1 Gatillante de la Citotoxidad Natural/metabolismo , Proteínas de Dominio T Box/genética , Proteínas de Dominio T Box/metabolismo
16.
Cell Rep ; 34(12): 108894, 2021 03 23.
Artículo en Inglés | MEDLINE | ID: mdl-33761361

RESUMEN

The process of hematopoiesis is subject to substantial ontogenic remodeling that is accompanied by alterations in cellular fate during both development and disease. We combine state-of-the-art mass spectrometry with extensive functional assays to gain insight into ontogeny-specific proteomic mechanisms regulating hematopoiesis. Through deep coverage of the cellular proteome of fetal and adult lympho-myeloid multipotent progenitors (LMPPs), common lymphoid progenitors (CLPs), and granulocyte-monocyte progenitors (GMPs), we establish that features traditionally attributed to adult hematopoiesis are conserved across lymphoid and myeloid lineages, whereas generic fetal features are suppressed in GMPs. We reveal molecular and functional evidence for a diminished granulocyte differentiation capacity in fetal LMPPs and GMPs relative to their adult counterparts. Our data indicate an ontogeny-specific requirement of myosin activity for myelopoiesis in LMPPs. Finally, we uncover an ontogenic shift in the monocytic differentiation capacity of GMPs, partially driven by a differential expression of Irf8 during fetal and adult life.


Asunto(s)
Linaje de la Célula , Células Madre Hematopoyéticas/citología , Células Madre Hematopoyéticas/metabolismo , Proteómica , Células Madre Adultas/citología , Células Madre Adultas/metabolismo , Animales , Diferenciación Celular , Feto/citología , Granulocitos/citología , Células HEK293 , Humanos , Inmunofenotipificación , Factores Reguladores del Interferón/metabolismo , Cinética , Células Progenitoras Linfoides/citología , Células Progenitoras Linfoides/metabolismo , Ratones Endogámicos C57BL , Monocitos/citología , Monocitos/metabolismo , Células Progenitoras Mieloides/citología , Células Progenitoras Mieloides/metabolismo , Proteoma/metabolismo , Quinasas Asociadas a rho/antagonistas & inhibidores , Quinasas Asociadas a rho/metabolismo
17.
Science ; 371(6536)2021 03 26.
Artículo en Inglés | MEDLINE | ID: mdl-33766856

RESUMEN

The pathways that lead to the development of tissue-resident lymphocytes, including liver type 1 innate lymphoid cells (ILC1s), remain unclear. We show here that the adult mouse liver contains Lin-Sca-1+Mac-1+ hematopoietic stem cells derived from the fetal liver. This population includes Lin-CD122+CD49a+ progenitors that can generate liver ILC1s but not conventional natural killer cells. Interferon-γ (IFN-γ) production by the liver ILC1s themselves promotes the development of these cells in situ, through effects on their IFN-γR+ liver progenitors. Thus, an IFN-γ-dependent loop drives liver ILC1 development in situ, highlighting the contribution of extramedullary hematopoiesis to regional immune composition within the liver.


Asunto(s)
Interferón gamma/metabolismo , Hígado/citología , Hígado/inmunología , Linfocitos/citología , Linfocitos/inmunología , Animales , Hematopoyesis Extramedular , Inmunidad Innata , Interferón gamma/genética , Células Asesinas Naturales/citología , Células Asesinas Naturales/inmunología , Células Progenitoras Linfoides/citología , Células Progenitoras Linfoides/metabolismo , Linfopoyesis , Ratones , Receptores de Interferón/genética , Receptores de Interferón/metabolismo , Transducción de Señal , Proteínas de Dominio T Box/metabolismo , Receptor de Interferón gamma
18.
Nat Commun ; 12(1): 1622, 2021 03 12.
Artículo en Inglés | MEDLINE | ID: mdl-33712608

RESUMEN

Our mathematical model of integration site data in clinical gene therapy supported the existence of long-term lymphoid progenitors capable of surviving independently from hematopoietic stem cells. To date, no experimental setting has been available to validate this prediction. We here report evidence of a population of lymphoid progenitors capable of independently maintaining T and NK cell production for 15 years in humans. The gene therapy patients of this study lack vector-positive myeloid/B cells indicating absence of engineered stem cells but retain gene marking in both T and NK. Decades after treatment, we can still detect and analyse transduced naïve T cells whose production is likely maintained by a population of long-term lymphoid progenitors. By tracking insertional clonal markers overtime, we suggest that these progenitors can support both T and NK cell production. Identification of these long-term lymphoid progenitors could be utilised for the development of next generation gene- and cancer-immunotherapies.


Asunto(s)
Células Asesinas Naturales/fisiología , Linfocitos/fisiología , Células Progenitoras Linfoides/fisiología , Linfocitos T/fisiología , Linfocitos B , Terapia Genética/métodos , Células Madre Hematopoyéticas , Humanos , Interferón gamma/metabolismo , Mutagénesis , Células Mieloides/fisiología , Proto-Oncogenes/genética , Proto-Oncogenes/fisiología
19.
Mol Biol Rep ; 48(1): 817-822, 2021 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-33438082

RESUMEN

Acute lymphoid leukemia (ALL) is a type of hematological neoplasm that affects the precursor cells of strains B, T  and NK, with a higher incidence in the pediatric range. The pathophysiology of ALL is characterized by chromosomal abnormalities and genetic alterations involved in the differentiation and proliferation of lymphoid precursor cells. Despite the lack of information in the literature, it is believed that leukemogenesis originates from a complex interaction between environmental and genetic factors, which combined lead to cellular modifications. Environmental factors have been evaluated as possible predisposing factors in the development of ALL but there are still conflicting results in the world literature. In this context, the aim of the present review is to discuss the major exogenous factors regarding ALL.


Asunto(s)
Carcinogénesis/inmunología , Regulación Leucémica de la Expresión Génica/inmunología , Interacción Gen-Ambiente , Células Progenitoras Linfoides/inmunología , Leucemia-Linfoma Linfoblástico de Células Precursoras/inmunología , Adulto , Linfocitos B/inmunología , Linfocitos B/patología , Carcinogénesis/genética , Carcinogénesis/patología , Diferenciación Celular , Proliferación Celular , Niño , Aberraciones Cromosómicas , Citocinas/genética , Citocinas/inmunología , Humanos , Células Asesinas Naturales/inmunología , Células Asesinas Naturales/patología , Células Progenitoras Linfoides/patología , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/inmunología , Leucemia-Linfoma Linfoblástico de Células Precursoras/etiología , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/patología , Linfocitos T/inmunología , Linfocitos T/patología
20.
Cell Rep ; 34(3): 108646, 2021 01 19.
Artículo en Inglés | MEDLINE | ID: mdl-33472062

RESUMEN

In mammals, hearing loss is irreversible due to the lack of regenerative potential of non-sensory cochlear cells. Neonatal cochlear cells, however, can grow into organoids that harbor sensory epithelial cells, including hair cells and supporting cells. Here, we purify different cochlear cell types from neonatal mice, validate the composition of the different groups with single-cell RNA sequencing (RNA-seq), and assess the various groups' potential to grow into inner ear organoids. We find that the greater epithelial ridge (GER), a transient cell population that disappears during post-natal cochlear maturation, harbors the most potent organoid-forming cells. We identified three distinct GER cell groups that correlate with a specific spatial distribution of marker genes. Organoid formation was synergistically enhanced when the cells were cultured at increasing density. This effect is not due to diffusible signals but requires direct cell-to-cell contact. Our findings improve the development of cell-based assays to study culture-generated inner ear cell types.


Asunto(s)
Cóclea/fisiología , Células Epiteliales/metabolismo , Organoides/metabolismo , Animales , Células Progenitoras Linfoides , Ratones
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