GSE107368
Transcription Factor p73 Regulates Th1 Differentiation
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 IFN? expression. Overexpression of p73 inhibited Th1 differentiation, as evaluated by reduced IFN? expression, whereas shRNA knockdown or knockout of the p73 gene augmented IFN? 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 IFN? expression, as deletion of p73 DNA binding domain abolished IFN? 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 IFN? expression, revealing a previously unanticipated role for p73 in Th1 cell differentiation. Overall design: mRNA expression and ChIP-Seq analysis.