The AP-1 factors FOSL1 and FOSL2 co-regulate human Th17 responses

Abstract

Th17 cells protect mucosal barriers, but their aberrant activity can cause autoimmunity. Molecular networks dictating human Th17 function are largely unexplored, and this hinders disease-studies. Here, we investigated the roles of the AP-1 factors, FOSL1 and FOSL2, in inducing human Th17 responses. Transient knockdown and over-expression strategies found the two proteins to inhibit Th17-cell identity, while revealing a distinct cooperativity between their functions. Strikingly, FOSL1 plays different roles in human and mouse and FOSL-mediated Th17 regulation is opposed by the AP-1 factor, BATF. Genome-wide occupancy analysis demonstrated the co-localization of FOSL1, FOSL2 and BATF in the vicinity of key Th17 genes. The functional interplay among these factors is possibly governed by sharing interactions with a common set of lineage-associated proteins. We further discovered that the genomic binding sites of these factors harbour a large number of disease-linked SNPs, many of which alter the ability of a given factor to bind DNA. Our findings thus provide crucial insights into the transcriptional regulation of human Th17 function and associated pathologies. ONE SENTENCE SUMMARYFOSL1- and FOSL2-mediated transcription during early human Th17 differentiation