Regulatory action of multiple AP-1 transcription factors balances Th17 lineage stability and plasticity

Abstract

Abstract During an immune response, naïve CD4+ T cells encounter their cognate antigen and are induced to differentiate into one of several distinct T helper (Th) subsets. Although previously regarded as lineage-committed, these differentiated subsets are now appreciated to exhibit a degree of plasticity, whereby certain environmental stimuli permit inter-subset conversion. In particular, Th17 cells have been demonstrated to exhibit a high degree of intrinsic plasticity and are capable of “reprogramming” towards phenotypes typical of both pro- and anti-inflammatory T cell subsets. Despite the suggested importance of this phenomenon in the etiology of autoimmune and inflammatory disorders, the mechanisms underlying Th17 cell plasticity are poorly understood. We have recently identified the AP-1 transcription factor family as a central controller of both Th17 cell stability and plasticity, with different AP-1 family members exhibiting both overlapping and unique control of distinct aspects of the Th17 transcriptional program. Using a combined strategy employing transcriptomics and global analysis of TF occupancy for multiple AP-1 family members, we have identified novel regulatory modules defined by distinct modes of AP-1-mediated activation. These findings provide new insights into the mechanism by which environmentally-regulated transcription factors collaborate for the maintenance of T cell identity.