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1.
Nat Commun ; 15(1): 7809, 2024 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-39242588

RESUMO

Innate lymphoid cells (ILCs) are critical in maintaining tissue homeostasis, and during infection and inflammation. Here we identify, by using combinatorial reporter mice, a rare ILC progenitor (ILCP) population, resident to the small intestinal lamina propria (siLP) in adult mice. Transfer of siLP-ILCP into recipients generates group 1 ILCs (including ILC1 and NK cells), ILC2s and ILC3s within the intestinal microenvironment, but almost exclusively group 1 ILCs in the liver, lung and spleen. Single cell gene expression analysis and high dimensional spectral cytometry analysis of the siLP-ILCPs and ILC progeny indicate that the phenotype of the group 1 ILC progeny is also influenced by the tissue microenvironment. Thus, a local pool of siLP-ILCP can contribute to pan-ILC generation in the intestinal microenvironment but has more restricted potential in other tissues, with a greater propensity than bone marrow-derived ILCPs to favour ILC1 and ILC3 production. Therefore, ILCP potential is influenced by both tissue of origin and the microenvironment during development. This may provide additional flexibility during the tuning of immune reactions.


Assuntos
Imunidade Inata , Mucosa Intestinal , Células Progenitoras Linfoides , Camundongos Endogâmicos C57BL , Animais , Camundongos , Mucosa Intestinal/imunologia , Mucosa Intestinal/citologia , Células Progenitoras Linfoides/citologia , Células Progenitoras Linfoides/metabolismo , Células Progenitoras Linfoides/imunologia , Microambiente Celular/imunologia , Linfócitos/imunologia , Intestino Delgado/imunologia , Intestino Delgado/citologia , Feminino , Masculino
2.
Elife ; 132024 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-39269281

RESUMO

We identified a novel mouse plasmacytoid dendritic cell (pDC) lineage derived from the common lymphoid progenitors (CLPs) that is dependent on expression of Bcl11a. These CLP-derived pDCs, which we refer to as 'B-pDCs', have a unique gene expression profile that includes hallmark B cell genes, normally not expressed in conventional pDCs. Despite expressing most classical pDC markers such as SIGLEC-H and PDCA1, B-pDCs lack IFN-α secretion, exhibiting a distinct inflammatory profile. Functionally, B-pDCs induce T cell proliferation more robustly than canonical pDCs following Toll-like receptor 9 (TLR9) engagement. B-pDCs, along with another homogeneous subpopulation of myeloid-derived pDCs, display elevated levels of the cell surface receptor tyrosine kinase AXL, mirroring human AXL+ transitional DCs in function and transcriptional profile. Murine B-pDCs therefore represent a phenotypically and functionally distinct CLP-derived DC lineage specialized in T cell activation and previously not described in mice.


Assuntos
Células Dendríticas , Animais , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Camundongos , Ativação Linfocitária , Linfócitos T/imunologia , Linfócitos T/metabolismo , Camundongos Endogâmicos C57BL , Perfilação da Expressão Gênica , Células Progenitoras Linfoides/metabolismo , Células Progenitoras Linfoides/citologia , Linhagem da Célula
4.
Nat Commun ; 15(1): 5910, 2024 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-39003273

RESUMO

Lymphoid specification in human hematopoietic progenitors is not fully understood. To better associate lymphoid identity with protein-level cell features, we conduct a highly multiplexed single-cell proteomic screen on human bone marrow progenitors. This screen identifies terminal deoxynucleotidyl transferase (TdT), a specialized DNA polymerase intrinsic to VDJ recombination, broadly expressed within CD34+ progenitors prior to B/T cell emergence. While these TdT+ cells coincide with granulocyte-monocyte progenitor (GMP) immunophenotype, their accessible chromatin regions show enrichment for lymphoid-associated transcription factor (TF) motifs. TdT expression on GMPs is inversely related to the SLAM family member CD84. Prospective isolation of CD84lo GMPs demonstrates robust lymphoid potentials ex vivo, while still retaining significant myeloid differentiation capacity, akin to LMPPs. This multi-omic study identifies human bone marrow lymphoid-primed progenitors, further defining the lympho-myeloid axis in human hematopoiesis.


Assuntos
DNA Nucleotidilexotransferase , Células Progenitoras Linfoides , Humanos , Antígenos CD/metabolismo , Antígenos CD/genética , Antígenos CD34/metabolismo , Diferenciação Celular , DNA Nucleotidilexotransferase/metabolismo , Hematopoese , Células-Tronco Hematopoéticas/metabolismo , Células-Tronco Hematopoéticas/citologia , Células Progenitoras Linfoides/metabolismo , Células Progenitoras Linfoides/citologia , Proteômica/métodos , Análise de Célula Única
5.
Nat Immunol ; 25(7): 1183-1192, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38872000

RESUMO

Natural killer (NK) cells function by eliminating virus-infected or tumor cells. Here we identified an NK-lineage-biased progenitor population, referred to as early NK progenitors (ENKPs), which developed into NK cells independently of common precursors for innate lymphoid cells (ILCPs). ENKP-derived NK cells (ENKP_NK cells) and ILCP-derived NK cells (ILCP_NK cells) were transcriptionally different. We devised combinations of surface markers that identified highly enriched ENKP_NK and ILCP_NK cell populations in wild-type mice. Furthermore, Ly49H+ NK cells that responded to mouse cytomegalovirus infection primarily developed from ENKPs, whereas ILCP_NK cells were better IFNγ producers after infection with Salmonella and herpes simplex virus. Human CD56dim and CD56bright NK cells were transcriptionally similar to ENKP_NK cells and ILCP_NK cells, respectively. Our findings establish the existence of two pathways of NK cell development that generate functionally distinct NK cell subsets in mice and further suggest these pathways may be conserved in humans.


Assuntos
Diferenciação Celular , Células Matadoras Naturais , Células Matadoras Naturais/imunologia , Animais , Camundongos , Humanos , Diferenciação Celular/imunologia , Camundongos Endogâmicos C57BL , Imunidade Inata , Antígeno CD56/metabolismo , Muromegalovirus/imunologia , Linhagem da Célula/imunologia , Interferon gama/metabolismo , Interferon gama/imunologia , Células Progenitoras Linfoides/metabolismo , Células Progenitoras Linfoides/citologia , Células Progenitoras Linfoides/imunologia , Camundongos Knockout , Células Cultivadas
6.
Trends Immunol ; 45(7): 495-510, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38908962

RESUMO

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.


Assuntos
Envelhecimento , Linfopoese , Humanos , Envelhecimento/imunologia , Células Progenitoras Linfoides/citologia , Células Progenitoras Linfoides/metabolismo , Células Progenitoras Linfoides/imunologia , Linfócitos B/imunologia , Animais , Diferenciação Celular , Células Matadoras Naturais/imunologia
7.
Sci Immunol ; 9(95): eadj2654, 2024 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-38820141

RESUMO

Tissue-resident innate lymphoid cells (ILCs) play a vital role in the frontline defense of various tissues, including the lung. The development of type 2 ILCs (ILC2s) depends on transcription factors such as GATA3, RORα, GFI1, and Bcl11b; however, the factors regulating lung-resident ILC2s remain unclear. Through fate mapping analysis of the paralog transcription factors GFI1 and GFI1B, we show that GFI1 is consistently expressed during the transition from progenitor to mature ILC2s. In contrast, GFI1B expression is limited to specific subsets of bone marrow progenitors and lung-resident ILC progenitors. We found that GFI1B+ lung ILC progenitors represent a multi-lineage subset with tissue-resident characteristics and the potential to form lung-derived ILC subsets and liver-resident ILC1s. Loss of GFI1B in bone marrow progenitors led to the selective loss of lung-resident IL-18R+ ILCs and mature ILC2, subsequently preventing the emergence of effector ILCs that could protect the lung against inflammatory or tumor challenge.


Assuntos
Imunidade Inata , Pulmão , Camundongos Endogâmicos C57BL , Proteínas Proto-Oncogênicas , Animais , Pulmão/imunologia , Pulmão/citologia , Camundongos , Imunidade Inata/imunologia , Proteínas Proto-Oncogênicas/imunologia , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/deficiência , Proteínas Proto-Oncogênicas/metabolismo , Células Progenitoras Linfoides/imunologia , Células Progenitoras Linfoides/citologia , Proteínas Repressoras/genética , Proteínas Repressoras/imunologia , Camundongos Knockout , Linfócitos/imunologia , Diferenciação Celular/imunologia , Proteínas de Ligação a DNA , Fatores de Transcrição
8.
Cell Rep ; 43(5): 114200, 2024 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-38717905

RESUMO

Innate lymphoid cells (ILCs), strategically positioned throughout the body, undergo population declines over time. A solution to counteract this problem is timely mobilization of multipotential progenitors from the bone marrow. It remains unknown what triggers the mobilization of bone marrow ILC progenitors (ILCPs). We report that ILCPs are regulated by the circadian clock to emigrate and generate mature ILCs in the periphery. We found that circadian-clock-defective ILCPs fail to normally emigrate and generate ILCs. We identified circadian-clock-controlled endocrine and cytokine cues that, respectively, regulate the retention and emigration of ILCPs at distinct times of each day. Activation of the stress-hormone-sensing glucocorticoid receptor upregulates CXCR4 on ILCPs for their retention in the bone marrow, while the interleukin-18 (IL-18) and RORα signals upregulate S1PR1 on ILCPs for their mobilization to the periphery. Our findings establish important roles of circadian signals for the homeostatic efflux of bone marrow ILCPs.


Assuntos
Relógios Circadianos , Animais , Camundongos , Citocinas/metabolismo , Camundongos Endogâmicos C57BL , Medula Óssea/metabolismo , Transdução de Sinais , Receptores CXCR4/metabolismo , Células da Medula Óssea/metabolismo , Células da Medula Óssea/citologia , Células Progenitoras Linfoides/metabolismo , Células Progenitoras Linfoides/citologia , Imunidade Inata , Movimento Celular , Membro 1 do Grupo F da Subfamília 1 de Receptores Nucleares/metabolismo , Membro 1 do Grupo F da Subfamília 1 de Receptores Nucleares/genética , Receptores de Glucocorticoides/metabolismo , Linfócitos/metabolismo , Linfócitos/imunologia
10.
Methods Mol Biol ; 2580: 211-232, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36374460

RESUMO

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).


Assuntos
Linfócitos , Linfócitos T , Camundongos , Animais , Imunidade Inata , Medula Óssea , Células Progenitoras Linfoides/metabolismo , Diferenciação Celular
11.
Cell Rep ; 41(5): 111569, 2022 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-36323259

RESUMO

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.


Assuntos
Imunidade Inata , Células-Tronco Pluripotentes , Animais , Linfócitos/metabolismo , Diferenciação Celular , Células Progenitoras Linfoides/metabolismo
12.
Front Immunol ; 13: 957711, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36268032

RESUMO

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.


Assuntos
Imunidade Inata , Linfócitos , Células Progenitoras Linfoides , Diferenciação Celular , Linfócitos B
13.
J Biol Chem ; 298(11): 102506, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-36126774

RESUMO

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.


Assuntos
Células Progenitoras Linfoides , Fatores de Transcrição , Células Progenitoras Linfoides/fisiologia , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Cromatografia Líquida , Espectrometria de Massas em Tandem , Células-Tronco Hematopoéticas/metabolismo , Diferenciação Celular , Proteínas com Domínio LIM/genética , Proteínas com Domínio LIM/metabolismo
14.
STAR Protoc ; 3(3): 101534, 2022 09 16.
Artigo em Inglês | MEDLINE | ID: mdl-35830307

RESUMO

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).


Assuntos
Imunidade Inata , Linfócitos , Animais , Medula Óssea , Células Progenitoras Linfoides , Camundongos , Linfócitos T
15.
Nat Commun ; 13(1): 4344, 2022 07 27.
Artigo em Inglês | MEDLINE | ID: mdl-35896601

RESUMO

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.


Assuntos
Imunidade Inata , Linfócitos , Diferenciação Celular , Humanos , Interleucina-23 , Células Matadoras Naturais , Células Progenitoras Linfoides/fisiologia , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/genética , Receptores Notch/metabolismo
16.
Front Immunol ; 13: 854312, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35757763

RESUMO

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.


Assuntos
Proteína Forkhead Box O1 , Proteína Forkhead Box O3 , Células Matadoras Naturais , Células Progenitoras Linfoides , Animais , Diferenciação Celular/imunologia , Proteína Forkhead Box O1/imunologia , Proteína Forkhead Box O3/imunologia , Imunidade Inata , Células Matadoras Naturais/citologia , Células Matadoras Naturais/imunologia , Células Progenitoras Linfoides/citologia , Células Progenitoras Linfoides/imunologia , Camundongos , Camundongos Endogâmicos C57BL
17.
Front Immunol ; 13: 880668, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35603175

RESUMO

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.


Assuntos
Hematopoese , Células Progenitoras Linfoides , Linfócitos B/metabolismo , Proteína Forkhead Box O1/genética , Proteína Forkhead Box O1/metabolismo , Hematopoese/genética , Células Progenitoras Linfoides/metabolismo , Células Precursoras de Linfócitos B/metabolismo
18.
J Immunol ; 208(5): 1066-1075, 2022 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-35140132

RESUMO

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.


Assuntos
Células Dendríticas/imunologia , Doença Enxerto-Hospedeiro/imunologia , Células Progenitoras Linfoides/citologia , Receptores de Fator Estimulador de Colônias de Granulócitos/metabolismo , Células T Auxiliares Foliculares/imunologia , Transferência Adotiva , Animais , Autoanticorpos/imunologia , Antígeno B7-1/biossíntese , Fatores de Transcrição de Zíper de Leucina Básica/genética , Antígenos CD4/biossíntese , Antígenos CD8/biossíntese , Diferenciação Celular/imunologia , Células Dendríticas/transplante , Feminino , Fator Estimulador de Colônias de Granulócitos/metabolismo , Interleucina-6/biossíntese , Ativação Linfocitária/imunologia , Células Progenitoras Linfoides/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores de Fator Estimulador de Colônias de Granulócitos/genética , Proteínas Repressoras/genética , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais/imunologia
19.
Int J Mol Sci ; 23(3)2022 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-35163045

RESUMO

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.


Assuntos
Perfilação da Expressão Gênica/métodos , Redes Reguladoras de Genes , Hematopoese , Células Progenitoras Linfoides/citologia , RNA Longo não Codificante/genética , Animais , Células Cultivadas , Feminino , Regulação da Expressão Gênica , Marcadores Genéticos , Sequenciamento de Nucleotídeos em Larga Escala , Células Progenitoras Linfoides/química , Masculino , Camundongos , Análise de Sequência de RNA
20.
Cell Rep ; 38(3): 110266, 2022 01 18.
Artigo em Inglês | MEDLINE | ID: mdl-35045305

RESUMO

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.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Diferenciação Celular/imunologia , Células Dendríticas/imunologia , Células Progenitoras Linfoides/imunologia , Receptores CXCR3/imunologia , Baço/imunologia , Animais , Camundongos , Infecção Persistente/imunologia , Toxoplasmose Animal/imunologia
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