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Transcription Factor RUNX3 Mediates Plasticity of ThGM Cells Toward Th1 Phenotype.

ABSTRACT: GM-CSF-producing T helper (Th) cells play a crucial role in the pathogenesis of autoimmune diseases such as multiple sclerosis (MS). Recent studies have identified a distinct population of GM-CSF-producing Th cells, named ThGM cells, that also express cytokines TNF, IL-2, and IL-3, but lack expression of master transcription factors (TF) and signature cytokines of commonly recognized Th cell lineages. ThGM cells are highly encephalitogenic in a mouse model of MS, experimental autoimmune encephalomyelitis (EAE). Similar to Th17 cells, in response to IL-12, ThGM cells upregulate expression of T-bet and IFN-γ and switch their phenotype to Th1. Here we show that in addition to T-bet, TF RUNX3 also contributes to the Th1 switch of ThGM cells. T-bet-deficient ThGM cells in the CNS of mice with EAE had low expression of RUNX3, and knockdown of RUNX3 expression in ThGM cells abrogated the Th1-inducing effect of IL-12. Comparison of ThGM and Th1 cell transcriptomes showed that ThGM cells expressed a set of TFs known to inhibit the development of other Th lineages. Lack of expression of lineage-specific cytokines and TFs by ThGM cells, together with expression of TFs that inhibit the development of other Th lineages, suggests that ThGM cells are a non-polarized subset of Th cells with lineage characteristics.

SUBMITTER: Rasouli J

PROVIDER: S-EPMC9289370 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Transcription factor RUNX3 mediates plasticity of ThGM cells toward Th1 phenotype.

Project description:GM-CSF-producing T helper (Th) cells play a crucial role in the pathogenesis of autoimmune diseases such as multiple sclerosis (MS). Recent studies have identified a distinct population of GM-CSF-producing Th cells, named ThGM cells, that also express cytokines TNF, IL-2, and IL-3, but lack expression of master transcription factors (TF) and signature cytokines of commonly recognized Th cell lineages. ThGM cells are highly encephalitogenic in a mouse model of MS, experimental autoimmune encephalomyelitis (EAE). Similar to Th17 cells, in response to IL-12, ThGM cells upregulate expression of T-bet and IFN-g and switch their phenotype to Th1. Here we show that in addition to T-bet, TF RUNX3 also contributes to the Th1 switch of ThGM cells. T-bet-deficient ThGM cells in the CNS of mice with EAE had low expression of RUNX3, and knockdown of RUNX3 expression in ThGM cells abrogated the Th1-inducing effect of IL-12. Comparison of ThGM and Th1 cell transcriptomes showed that ThGM cells expressed a set of TFs known to inhibit the development of other Th lineages. Lack of expression of lineage-specific cytokines and TFs by ThGM cells, together with expression of TFs that inhibit the development of other Th lineages, suggests that ThGM cells are a non-polarized subset of Th cells with lineage characteristics.

2022-07-27 | GSE205763 | GEO

Transcription factor RUNX3 mediates plasticity of ThGM cells toward Th1 phenotype.

Project description:Transcription factor RUNX3 mediates plasticity of ThGM cells toward Th1 phenotype.

| PRJNA847542 | ENA

Twist1 regulates Ifng expression in Th1 cells by interfering with Runx3 function.

Project description:A transcription factor network that includes STAT4, T-bet, and Runx3 promotes the differentiation of Th1 cells and inflammatory immune responses. How additional transcription factors regulate the function of Th1 cells has not been defined. In this study we show that the negative regulatory factor Twist1 decreases expression of T-bet, Runx3, and IL-12R?2 as it inhibits IFN-? production. Ectopic expression of Runx3, but not T-bet or IL-12R?2, compensates for the effects of Twist1 on IFN-? production, and Twist1 regulation of Ifng depends on complex formation with Runx3. Twist1 decreases Runx3 and T-bet binding at the Ifng locus, and it decreases chromatin looping within the Ifng locus. These data define an IL-12/STAT4-induced negative regulatory loop that impacts multiple components of the Th1 transcriptional network and provide further insight into regulation of Th1 differentiation.

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Transcription factor p73 regulates Th1 differentiation.

Project description:Inter-individual differences in T helper (Th) cell responses affect susceptibility to infectious, allergic and autoimmune diseases. To identify factors contributing to these response differences, here we analyze in vitro differentiated Th1 cells from 16 inbred mouse strains. Haplotype-based computational genetic analysis indicates that the p53 family protein, p73, affects Th1 differentiation. In cells differentiated under Th1 conditions in vitro, p73 negatively regulates IFNγ production. p73 binds within, or upstream of, and modulates the expression of Th1 differentiation-related genes such as Ifng and Il12rb2. Furthermore, in mouse experimental autoimmune encephalitis, p73-deficient mice have increased IFNγ production and less disease severity, whereas in an adoptive transfer model of inflammatory bowel disease, transfer of p73-deficient naïve CD4+ T cells increases Th1 responses and augments disease severity. Our results thus identify p73 as a negative regulator of the Th1 immune response, suggesting that p73 dysregulation may contribute to susceptibility to autoimmune disease.

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Transcription Factor Runx3 Is Induced by Influenza A Virus and Double-Strand RNA and Mediates Airway Epithelial Cell Apoptosis.

Project description:Influenza A virus (IAV) targets airway epithelial cells and exploits the host cell machinery to replicate, causing respiratory illness in annual epidemics and pandemics of variable severity. The high rate of antigenic drift (viral mutation) and the putative antigenic shift (reassortant strains) have raised the need to find the host cell inducible factors modulating IAV replication and its pathogenesis to develop more effective antiviral treatment. In this study, we found for the first time that transcription factor Runx3, a developmental regulator and tumor suppressor, was induced by IAV H1N1 and H3N2, viral RNA, a synthetic analog of viral double-stranded RNA (dsRNA) polyinosinic-polycytidylic acid, and type-II interferon-? (IFN?) in human airway epithelial cells. Whereas Runx3 was essentially not induced by type-I IFN? and type-III IFN?, we show that Runx3 induction by IAV infection and viral RNA is mediated through the innate immune receptor MDA5 and the I?B kinase-?-NF-?B pathway. Moreover, we provide substantial evidence indicating that Runx3 plays a crucial role in airway epithelial cell apoptosis induced by IAV infection and dsRNA through the activation of extrinsic and intrinsic apoptosis pathways. Thus, we have identified Runx3 as an inducible and important transcription factor modulating IAV-induced host epithelial cell apoptosis.

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The transcription factors Runx3 and ThPOK cross-regulate acquisition of cytotoxic function by human Th1 lymphocytes.

Project description:Cytotoxic CD4 (CD4CTX) T cells are emerging as an important component of antiviral and antitumor immunity, but the molecular basis of their development remains poorly understood. In the context of human cytomegalovirus infection, a significant proportion of CD4 T cells displays cytotoxic functions. We observed that the transcriptional program of these cells was enriched in CD8 T cell lineage genes despite the absence of ThPOK downregulation. We further show that establishment of CD4CTX-specific transcriptional and epigenetic programs occurred in a stepwise fashion along the Th1-differentiation pathway. In vitro, prolonged activation of naive CD4 T cells in presence of Th1 polarizing cytokines led to the acquisition of perforin-dependent cytotoxic activity. This process was dependent on the Th1 transcription factor Runx3 and was limited by the sustained expression of ThPOK. This work elucidates the molecular program of human CD4CTX T cells and identifies potential targets for immunotherapy against viral infections and cancer.

| S-EPMC5844691 | biostudies-literature

The transcription factor Fezf2 directs the differentiation of neural stem cells in the subventricular zone toward a cortical phenotype.

Project description:Postnatal neurogenesis in mammals is confined to restricted brain regions, including the subventricular zone (SVZ). In rodents, the SVZ is a lifelong source of new neurons fated to migrate to the olfactory bulb (OB), where the majority become GABAergic interneurons. The plastic capacity of neonatal and adult SVZ stem/progenitor cells is still largely unknown. By overexpressing the transcription factor Fezf2, a powerful master gene specifying the phenotype of glutamatergic subcerebral projecting neurons, we investigated whether the fate of postnatally generated SVZ neurons can be altered. Following lentiviral delivery of Fezf2 in the neonatal and adult SVZ niche, we showed that ectopic Fezf2 expression is sufficient to redirect the fate of SVZ stem cells. Thus, based on in vivo and in vitro experiments, we provide evidence that numerous Fezf2-positive OB neurons expressed glutamatergic pyramidal cell molecular markers instead of developing a GABAergic identity. Overexpression of Fezf2 had no effect on transit-amplifying progenitors or neuroblasts but was restricted to neural stem cells. Fezf2-respecified neurons bore features of pyramidal cells, exhibiting a larger cell body and a more elaborate dendritic tree, compared with OB granule cells. Patch-clamp recordings further indicated that Fezf2-respecified neurons had synaptic properties and a firing pattern reminiscent of a pyramidal cell-like phenotype. Together, the results demonstrate that neonatal and adult SVZ stem cells retain neuronal fate plasticity.

| S-EPMC4115522 | biostudies-literature

Follicular T Cells from smB<sup>-</sup> Common Variable Immunodeficiency Patients Are Skewed Toward a Th1 Phenotype.

Project description:Germinal center follicular T helper (GCTfh) cells are essential players in the differentiation of B cells. Circulating follicular T helper (cTfh) cells share phenotypic and functional properties with GCTfh cells. Distinct subpopulations of cTfh with different helper capabilities toward B cells can be identified: cTfh1 (CXCR3+CCR6-), cTfh2 (CXCR3-CCR6-), and cTfh17 (CXCR3-CCR6+). Alterations in cTfh function and/or distribution have been associated with autoimmunity, infectious diseases, and more recently, with several monogenic immunodeficiencies. Common variable immunodeficiency (CVID) disease is the commonest symptomatic primary immunodeficiency with a genetic cause identified in only 2-10% of patients. Although a heterogeneous disease, most patients show a characteristic defective B cell differentiation into memory B cells or antibody-secreting cells. We investigated if alterations in CVID cTfh cells frequency or distribution into cTfh1, cTfh2, and cTfh17 subpopulations and regulatory follicular T (Tfr) cells could be related to defects in CVID B cells. We found increased percentages of cTfh exhibiting higher programmed death-1 expression and altered subpopulations distribution in smB- CVID patients. In contrast to smB+ patients and controls, cTfh from smB- CVID patients show increased cTfh1 and decreased cTfh17 subpopulation percentages and increased CXCR3+CCR6+ cTfh, a population analogous to the recently described pathogenic Th17.1. Moreover, Tfr cells are remarkably decreased only in smB- CVID patients. In conclusion, increased cTfh17.1 and cTfh1/cTfh17 ratio in CVID patients could influence B cell fate in smB- CVID patients, with a more compromised B cell compartment, and the decrease in Tfr cells may lead to high risk of autoimmune conditions in CVID patients.

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MicroRNA124-IL6R Mediates the Effect of Nicotine in Inflammatory Bowel Disease by Shifting Th1/Th2 Balance Toward Th1.

Project description:Epidemiological investigations have shown that smoking ameliorates ulcerative colitis (UC) but exacerbates Crohn's disease (CD), diseases that feature a Th2-mediated and Th1-mediated response, respectively. Cigarette extracts, especially nicotine, affect the Th1/Th2 balance. We previously reported that nicotine protects against mouse DSS colitis (similar to UC) by enhancing microRNA-124 (miR-124) expression. Intriguingly, elevation of miR-124 in CD is reported to aggravate the disease. Here we investigate the dual regulation of miR-124 in inflammatory bowel diseases (IBDs), which may explain the similar bidirectional regulation of tobacco. We found that overexpressed miR-124 protected against mouse DSS-induced colitis with a Th1 polarization in peripheral blood lymphocytes and colon tissues, which was also found in human peripheral blood lymphocytes. Conversely, miR-124 knockdown worsened DSS murine colitis with a Th2 polarization. Moreover, knockdown of miR-124 could eliminate the polarization toward Th1 after nicotine treatment, suggesting that miR-124 mediates the effect of nicotine on the Th1/Th2 balance. In addition, interference of IL-6R, which is a downstream target of miR-124, could remarkably weaken the Th1 polarization induced by miR-124. Taken together, these results suggest that nicotine shifts the balance of Th1/Th2 toward Th1 via a miR-124-mediated IL-6R pathway, which might explain its dual role in IBDs.

| S-EPMC7050625 | biostudies-literature

Transcription factor Runx3 regulates interleukin-15-dependent natural killer cell activation.

Project description:Natural killer cells belong to the family of innate lymphoid cells comprising the frontline defense against infected and transformed cells. Development and activation of natural killer cells is highly dependent on interleukin-15 signaling. However, very little is known about the transcription program driving this process. The transcription factor Runx3 is highly expressed in natural killer cells, but its function in these cells is largely unknown. We show that loss of Runx3 impaired interleukin-15-dependent accumulation of mature natural killer cells in vivo and under culture conditions and pregnant Runx3(-/-) mice completely lack the unique population of interleukin-15-dependent uterine natural killer cells. Combined chromatin immunoprecipitation sequencing and differential gene expression analysis of wild-type versus Runx3-deficient in vivo activated splenic natural killer cells revealed that Runx3 cooperates with ETS and T-box transcription factors to drive the interleukin-15-mediated transcription program during activation of these cells. Runx3 functions as a nuclear regulator during interleukin-15-dependent activation of natural killer cells by regulating the expression of genes involved in proliferation, maturation, and migration. Similar studies with additional transcription factors will allow the construction of a more detailed transcriptional network that controls natural killer cell development and function.

| S-EPMC3958033 | biostudies-literature

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