C-Maf and STAT3 are essential but distinct regulators of RORγt+ and follicular regulatory T cells

Abstract

Abstract Foxp3+ regulatory T cells (Tregs) must adapt to function within a wide range of tissue environments and types of immune response. This flexibility is achieved through specialization, whereby context-dependent transcriptional changes integrate unique functionality into general Treg programming. In the most well-studied examples, this involves the co-expression of Foxp3 and another “lineage-defining” transcription factor (TF) which confers expression of specific functional genes. Two such specialized populations are RORγt+ Tregs and Bcl-6+ T follicular regulatory (Tfr) cells, which have important functions in regulating colitis and humoral immune responses, respectively. Although the importance of Treg specialization is now clear, the underlying network of signals and TFs driving this process is largely undefined. Here, we identify the TF c-Maf as an essential regulator of Treg specialization for both RORγt+ Tregs and Tfr cells. Importantly, the role of c-Maf in these subsets is highly specific, because deletion of Maf does not affect general Treg development, generation of other specialized Tregs, or expression of suppressive molecules. In vitro, we show that addition of IL-6 to Treg-promoting conditions is sufficient to drive both c-Maf expression and c-Maf-dependent conversion of naïve T cells to RORγt+ Tregs, suggesting that IL-6 might drive c-Maf in vivo. Surprisingly, although STAT3 – the primary downstream effector of IL-6 – is required for development of both RORγt+ Tregs and Tfr cells, we find that Stat3 deletion in vivo does not ablate c-Maf expression and results in Treg defects distinct from Maf deletion. Therefore, c-Maf and STAT3 are cooperative, but distinct regulators of RORγt+ and follicular Treg development.