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Effector differentiation downstream of lineage commitment in ILC1s is driven by Hobit across tissues.

ABSTRACT: Innate lymphoid cells (ILCs) participate in tissue homeostasis, inflammation, and early immunity against infection. It is unclear how ILCs acquire effector function and whether these mechanisms differ between organs. Through multiplexed single-cell mRNA sequencing, we identified cKit⁺CD127^hiTCF-1^hi early differentiation stages of T-bet⁺ ILC1s. These cells were present across different organs and had the potential to mature toward CD127^intTCF-1^int and CD127^-TCF-1^- ILC1s. Paralleling a gradual loss of TCF-1, differentiating ILC1s forfeited their expansion potential while increasing expression of effector molecules, reminiscent of T cell differentiation in secondary lymphoid organs. The transcription factor Hobit was induced in TCF-1^hi ILC1s and was required for their effector differentiation. These findings reveal sequential mechanisms of ILC1 lineage commitment and effector differentiation that are conserved across tissues. Our analyses suggest that ILC1s emerge as TCF-1^hi cells in the periphery and acquire a spectrum of organ-specific effector phenotypes through a uniform Hobit-dependent differentiation pathway driven by local cues.

SUBMITTER: Friedrich C

PROVIDER: S-EPMC7611762 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Effector differentiation downstream of lineage commitment in ILC1 is driven by Hobit across tissues.

Project description:Innate lymphoid cells (ILCs) mediate early immunity against infection and participate in tissue inflammation and homeostasis. It is unclear how ILCs acquire effector function, and whether these mechanisms differ between organs. Through multiplexed single-cell mRNA-sequencing we identified cKit+CD127hiTCF-1hi early differentiation stages of T-bet+ ILC1. These cells were present across different organs and had the potential to mature towards CD127intTCF-1int and CD127-TCF-1- ILC1. Paralleling a gradual loss of TCF-1, differentiating ILC1 forfeited their expansion potential while increasing expression of effector molecules, reminiscent of T cell differentiation in secondary lymphoid organs. The transcription factor Hobit was induced in TCF-1hi ILC1s and was required for their effector differentiation. These findings reveal sequential mechanisms of ILC1 lineage commitment and ILC1 effector differentiation that are conserved across tissues. Our analyses suggest that ILC1 emerge as TCF-1hi cells in the periphery and acquire a spectrum of organ-specific effector phenotypes through a uniform Hobit-dependent differentiation pathway driven by local cues.

2021-07-27 | GSE163452 | GEO

Effector differentiation downstream of lineage commitment in ILC1 is driven by Hobit across tissues.

Project description:Effector differentiation downstream of lineage commitment in ILC1 is driven by Hobit across tissues.

| PRJNA686131 | ENA

Hobit and Blimp-1 instruct the differentiation of iNKT cells into resident-phenotype lymphocytes after lineage commitment.

Project description:iNKT cells are CD1d-restricted T cells that play a pro-inflammatory or regulatory role in infectious and autoimmune diseases. Thymic precursors of iNKT cells eventually develop into distinct iNKT1, iNKT2, and iNKT17 lineages in the periphery. It remains unclear whether iNKT cells retain developmental potential after lineage commitment. iNKT cells acquire a similar phenotype as tissue-resident memory T cells, suggesting that they also differentiate along a trajectory that enables them to persist in peripheral tissues. Here, we addressed whether lineage commitment and memory differentiation are parallel or sequential developmental programs of iNKT cells. We defined three subsets of peripheral iNKT cells using CD62L and CD69 expression that separate central, effector, and resident memory phenotype cells. The majority of iNKT1 cells displayed a resident phenotype in contrast to iNKT2 and iNKT17 cells. The transcription factor Hobit, which is upregulated in iNKT cells, plays an essential role in their development together with its homolog Blimp-1. Hobit and Blimp-1 instructed the differentiation of central memory iNKT cells into resident memory iNKT cells, but did not impact commitment into iNKT1, iNKT2, or iNKT17 lineages. Thus, we conclude that memory differentiation and the establishment of residency occur after lineage commitment through a Hobit and Blimp-1-driven transcriptional program.

| S-EPMC9305946 | biostudies-literature

Single-molecule analysis of myocyte differentiation reveals bimodal lineage commitment.

Project description:Cell differentiation is the foundation for tissue development and regeneration, disease modeling, and cell-based therapies. Although the differentiation of cell populations has been extensively studied in many systems, much less is known about the distribution of decision making of single cells within these populations. To characterize the differentiation of single skeletal muscle cells, we used single-molecule mRNA fluorescence in situ hybridization (smFISH) to precisely quantify the expression levels of the master myogenic regulatory factors MyoD and myogenin in individual myoblasts. We identified distinct cell states characterized by the number of myogenin transcripts expressed by a cell, with myoblasts stochastically transitioning to a myogenin-high state during differentiation. We also used MyoD overexpression to force the transdifferentiation of C3H10T1/2 cells into an induced myoblast phenotype. These reprogrammed cells revealed the presence of a critical threshold of MyoD expression required to initiate myogenin expression. These results provide quantitative single-molecule data to support the model of switch-like cell decision making and lineage specification.

| S-EPMC4461500 | biostudies-other

IRF8 regulates B-cell lineage specification, commitment, and differentiation.

Project description:PU.1, IKAROS, E2A, EBF, and PAX5 comprise a transcriptional network that orchestrates B-cell lineage specification, commitment, and differentiation. Here we identify interferon regulatory factor 8 (IRF8) as another component of this complex, and show that it also modulates lineage choice by hematopoietic stem cells (HSCs). IRF8 binds directly to an IRF8/Ets consensus sequence located in promoter regions of Sfpi1 and Ebf1, which encode PU.1 and EBF, respectively, and is associated with transcriptional repression of Sfpi1 and transcriptional activation of Ebf1. Bone marrows of IRF8 knockout mice (IRF8(-/-)) had significantly reduced numbers of pre-pro-B cells and increased numbers of myeloid cells. Although HSCs of IRF8(-/-) mice failed to differentiate to B220(+) B-lineage cells in vitro, the defect could be rescued by transfecting HSCs with wild-type but not with a signaling-deficient IRF8 mutant. In contrast, overexpression of IRF8 in HSC-differentiated progenitor cells resulted in growth inhibition and apoptosis. We also found that IRF8 was expressed at higher levels in pre-pro-B cells than more mature B cells in wild-type mice. Together, these results indicate that IRF8 modulates lineage choice by HSCs and is part of the transcriptional network governing B-cell lineage specification, commitment, and differentiation.

| S-EPMC2581985 | biostudies-literature

Discrete regulatory modules instruct hematopoietic lineage commitment and differentiation.

Project description:Lineage commitment and differentiation is driven by the concerted action of master transcriptional regulators at their target chromatin sites. Multiple efforts have characterized the key transcription factors (TFs) that determine the various hematopoietic lineages. However, the temporal interactions between individual TFs and their chromatin targets during differentiation and how these interactions dictate lineage commitment remains poorly understood. Here we perform dense, daily, temporal profiling of chromatin accessibility (DNase I-seq) and gene expression changes (total RNA-seq) along ex vivo human erythropoiesis to comprehensively define developmentally regulated DNase I hypersensitive sites (DHSs) and transcripts. We link both distal DHSs to their target gene promoters and individual TFs to their target DHSs, revealing that the regulatory landscape is organized in distinct sequential regulatory modules that regulate lineage restriction and maturation. Finally, direct comparison of transcriptional dynamics (bulk and single-cell) and lineage potential between erythropoiesis and megakaryopoiesis uncovers differential fate commitment dynamics between the two lineages as they exit the stem and progenitor stage. Collectively, these data provide insights into the temporally regulated synergy of the cis- and the trans-regulatory components underlying hematopoietic lineage commitment and differentiation.

| S-EPMC8611072 | biostudies-literature

The mTOR kinase differentially regulates effector and regulatory T cell lineage commitment.

Project description:Effector T cell differentiation requires the simultaneous integration of multiple, and sometimes opposing, cytokine signals. We demonstrated mTOR's role in dictating the outcome of T cell fate. mTOR-deficient T cells displayed normal activation and IL-2 production upon initial stimulation. However, such cells failed to differentiate into T helper 1 (Th1), Th2, or Th17 effector cells. The inability to differentiate was associated with decreased STAT transcription factor activation and failure to upregulate lineage-specific transcription factors. Under normally activating conditions, T cells lacking mTOR differentiated into Foxp3(+) regulatory T cells. This was associated with hyperactive Smad3 activation in the absence of exogenous TGF-beta. Surprisingly, T cells selectively deficient in TORC1 do not divert to a regulatory T cell pathway, implicating both TORC1 and TORC2 in preventing the generation of regulatory T cells. Overall, our studies suggest that mTOR kinase signaling regulates decisions between effector and regulatory T cell lineage commitment.

| S-EPMC2768135 | biostudies-literature

Signaling networks that control the lineage commitment and differentiation of bone cells.

Project description:Osteoblasts and osteoclasts are the two major bone cells involved in the bone remodeling process. Osteoblasts are responsible for bone formation while osteoclasts are the bone-resorbing cells. The major event that triggers osteogenesis and bone remodeling is the transition of mesenchymal stem cells into differentiating osteoblast cells and monocyte/macrophage precursors into differentiating osteoclasts. Imbalance in differentiation and function of these two cell types will result in skeletal diseases such as osteoporosis, Paget's disease, rheumatoid arthritis, osteopetrosis, periodontal disease, and bone cancer metastases. Osteoblast and osteoclast commitment and differentiation are controlled by complex activities involving signal transduction and transcriptional regulation of gene expression. Recent advances in molecular and genetic studies using gene targeting in mice enable a better understanding of the multiple factors and signaling networks that control the differentiation process at a molecular level. This review summarizes recent advances in studies of signaling transduction pathways and transcriptional regulation of osteoblast and osteoclast cell lineage commitment and differentiation. Understanding the signaling networks that control the commitment and differentiation of bone cells will not only expand our basic understanding of the molecular mechanisms of skeletal development but will also aid our ability to develop therapeutic means of intervention in skeletal diseases.

| S-EPMC3392028 | biostudies-literature

A cell-intrinsic role for CaMKK2 in granulocyte lineage commitment and differentiation.

Project description:Granulocytes serve a critical function in host organisms by recognizing and destroying invading microbes, as well as propagating and maintaining inflammation at sites of infection. However, the molecular pathways underpinning the development of granulocytes are poorly understood. Here, we identify a role for CaMKK2 in the restriction of granulocytic fate commitment and differentiation of myeloid progenitor cells. Following BMT, engraftment by Camkk2(-/-) donor cells resulted in the increased production of mature granulocytes in the BM and peripheral blood. Similarly, Camkk2(-/-) mice possessed elevated numbers of CMP cells and exhibited an accelerated granulopoietic phenotype in the BM. Camkk2(-/-) myeloid progenitors expressed increased levels of C/EBP? and PU.1 and preferentially differentiated into Gr1(+)Mac1(+) granulocytes and CFU-G in vitro. During normal granulopoiesis in vivo or G-CSF-induced differentiation of 32D myeloblast cells in vitro, CaMKK2 mRNA and protein were decreased as a function of time and were undetectable in mature granulocytes. Expression of ectopic CaMKK2 in Camkk2(-/-) CMPs was sufficient to rescue aberrant granulocyte differentiation and when overexpressed in 32D cells, was also sufficient to impede granulocyte differentiation in a kinase activity-dependent manner. Collectively, our results reveal a novel role for CaMKK2 as an inhibitor of granulocytic fate commitment and differentiation in early myeloid progenitors.

| S-EPMC3206468 | biostudies-literature

Dendrobium officinale polysaccharides regulate age-related lineage commitment between osteogenic and adipogenic differentiation.

Project description:ObjectivesExcessive oxidative stress and diminished antioxidant defences could contribute to age-related tissue damage and various diseases including age-related osteoporosis. Dendrobium officinale polysaccharides (DOPs), a major ingredient from a traditional Chinese medicine, have a great potential of antioxidative activity. In this study, we explore the role of DOP in age-related osteoporosis that remains elusive.Materials and methodsOxidative stimulation and DOP were used to treat bone marrow mesenchymal stem cells (BMSCs), whose lineage commitment was measured by adipogenic- and osteoblastic-induced differentiation analysis. The oxidative stress and antioxidant capacity of BMSCs under the treatment of DOP were analysed by the level of MDA, SOD. Related mechanism studies were confirmed by qRT-PCR, Western blotting and siRNA transfection. DOP was orally administrated in aged mice whose phenotype was confirmed by micro-CT, immunofluorescence, immunochemistry and calcein double-labelling analysis.ResultsDendrobium officinale polysaccharide treatment markedly increased osteogenic differentiation of BMSCs, while inhibiting adipogenic differentiation. In vitro, DOP could rescue H2O2-induced switch of BMSCs differentiation fate. However, this effect was abolished in BMSCs when interfered with Nrf2 siRNA. Furthermore, administration of DOP to aged mice significantly increased the bone mass and reduced the marrow adipose tissue (MAT) accompanied with decreased oxidative stress of BMSCs.ConclusionsOur study reveals that DOP can attenuate bone loss and MAT accumulation through NRF2 antioxidant signalling, which may represent as potential therapeutic agent for age-related osteoporosis.

| S-EPMC6668967 | biostudies-literature

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