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Transcription Factor p73 Regulates Th1 Differentiation

ABSTRACT: 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, we analyzed the phenotypic profiles of in vitro-differentiated Th1 cells from 16 inbred mouse strains. Haplotype-based computational genetic analysis indicated that the p53 family protein, p73, affected Th1 differentiation. In cells differentiated under Th1 conditions in vitro, we demonstrated that p73 was a negative regulator of IFNγ production, and this effect required the DNA-binding activity of p73. p73 bound within the gene body or upstream of many genes that affect Th1 differentiation and regulated their expression (e.g., Ifng and Il12rb2). Furthermore, in experimental autoimmune encephalitis, which is a mouse disease model of multiple sclerosis, p73-deficient mice had increased IFNg production and decreased disease severity, whereas in the adoptive transfer model of inflammatory bowel disease, transfer of p73- deficient naïve CD4+ T cells into WT Rag2-/- hosts resulted in increased Th1 responses and enhanced disease severity compared to transfer of WT cells. These studies identify p73 as a regulator of immune responses and indicate that its dysregulation may play a role in susceptibility to autoimmune disease.

ORGANISM(S): Mus musculus

PROVIDER: GSE144496 | GEO | 2020/01/29

REPOSITORIES: GEO

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Transcription Factor p73 Regulates Th1 Differentiation

Project description:T helper (Th) cells play critical functions in response to infectious, allergic, and autoimmune diseases. Upon exposure to a given infectious agent or stimulus, different individuals vary in their Th cell responses, influencing the final disease outcome. To investigate the genetic factors that contribute to such differential immune responses, we performed a haplotype-based computational genetic analysis based on the phenotypic profiles of in vitro differentiated Th1 cells from 16 inbred mouse strains. And we identified genes including that encoding the p53 family protein, p73, with SNP patterns that correlated with the quantitative difference in IFNγ expression. Overexpression of p73 inhibited Th1 differentiation, as evaluated by reduced IFNγ expression, whereas shRNA knockdown or knockout of the p73 gene augmented IFNγ production. An inhibitory effect of p73 on Th1 differentiation was also observed in Stat1-/- cells, indicating that the effect was at least partially independent of STAT1. The DNA-binding activity of p73 is required for its inhibitory effect on IFNγ expression, as deletion of p73 DNA binding domain abolished IFNγ inhibition. A global gene expression analysis showed that 206 genes are differentially expressed more than two-fold in response to p73 overexpression, and 55 of these are direct target genes of p73 in Th1 cells, based on ChIP-seq analysis. p73 binding peaks were identified at a range of genes, including at the Il12rb2, Il24, and Il2ra loci, and p73 was implicated for regulating these genes based on reporter constructs containing WT or mutant p73 binding sites. Furthermore, p73 deficient mice had reduced disease severity in MOG induced EAE, with increased IFNg production from spinal cord infiltrating cells. Thus, p73 is a novel regulator of IFNγ expression, revealing a previously unanticipated role for p73 in Th1 cell differentiation.

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The X chromosome gene Kdm6a modulates multiple immune response genes in CD4+ T cells and is disease-promoting in autoimmune disease

Project description:Multiple sclerosis (MS) is a T-cell mediated autoimmune disease that has a sexually dimorphic pattern in disease susceptibility. Consistent with many autoimmune diseases, females are more susceptible than males to MS. Sexual dimorphisms may be due to differences in sex hormones, sex chromosome genes, or both. Regarding sex chromosome genes, a small percentage of X chromosome genes escape the dosage compensation mechanism of X inactivation and have higher expression in females (XX) compared to males (XY). According to the high throughput analysis, the top sexually dimorphic gene with higher expression in CD4+ T cells from females (vs. males) and from XX mice (vs. XY) was Kdm6a, a histone demethylase and transcription factor on the X chromosome. Deletion of Kdm6a specifically in CD4+ T cells ameliorated clinical disease and reduced neuropathology in the classic CD4+ T cell mediated autoimmune disease, experimental autoimmune encephalomyelitis (EAE). Global transcriptome analysis in CD4+ T cells from EAE mice with a specific deletion of Kdm6a showed upregulation of Th2 and Th1 activation pathways and downregulation of neuroinflammation signaling pathways. Together, this demonstrates that the X escapee Kdm6a regulates multiple immune response genes, providing a mechanism for sex differences in autoimmune disease susceptibility.

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The X chromosome gene Kdm6a modulates multiple immune response genes in CD4+ T cells and is disease promoting in autoimmune disease

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Transcription Factor p73 Regulates Th1 Differentiation

Project description:Transcription Factor p73 Regulates Th1 Differentiation

| PRJNA603788 | ENA

Transcription Factor p73 Regulates Th1 Differentiation

Project description:Transcription Factor p73 Regulates Th1 Differentiation

| PRJNA419910 | ENA

Hypoxia-sensing by Colitogenic CD4+ T cells Is Regulated by the Histone Demethylase UTX [H3K27me3 CUT&Tag]

Project description:Hypoxia exacerbates tissue damage in inflammatory bowel disease (IBD). To counteract the deleterious effects of oxygen deprivation, cells within hypoxic tissues activate multiple adaptive mechanisms. Much attention has focused on adaptive pathways regulated by HIF (hypoxia inducible factor) transcription factors, and pharmacologic HIF stabilization is a promising therapeutic approach for IBD. However, recent evidence suggests that hypoxia-induction of cellular transcriptional programs can be mediated not only by HIF transcription factors, but also by oxygen-sensing epigenetic regulator, UTX. Here, we identify a key role for an UTX in modulating colitis severity. Unlike HIF-mediated pathways that act on gut epithelial cells, UTX-mediated pathways function in a T cell-intrinsic manner to protect against colitis. Hypoxia impairs the histone demethylase activity of UTX, which leads to accumulation of repressive H3K27me3 marks at IL12/STAT4 pathway genes (Il12rb2, Tbx21, and Ifng), decreased CD4+ T cell IFN-γ production, and increased CD4+ regulatory T cells (Tregs). Moreover, T cell specific UTX deletion protects mice from autoimmune colitis, which demonstrates that deactivation of UTX restores immune regulation in hypoxia-associated inflammation. Together these findings suggest that modulating UTX’s histone demethylase activity in T cells may be a new pharmacologic target for harnessing hypoxia-induced adaptive pathways in colitis.

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