A Cellular and Molecular View of T Helper 17 cell Plasticity in Autoimmunity

Since the original identification of the T helper 17 (Th17) subset in 2005, it has become evident that these cells do not only contribute to host defence against pathogens, such as bacteria and fungi, but that they are also critically involved in the pathogenesis of many autoimmune diseases. In contrast to the classic Th1 and Th2 cells, which represent rather stably polarized subsets, Th17 cells display remarkable heterogeneity and plasticity. This has been attributed to the characteristics of the key transcription factor that guides Th17 differentiation, retinoic acid receptor-related orphan nuclear receptor gamma (RORγ). Unlike the 'master regulators' T-bet and GATA3 that orchestrate Th1 and Th2 differentiation, respectively, RORγ controls transcription at relatively few loci in Th17 cells. Moreover, its expression is not stabilized by positive feedback loops but rather influenced by environmental cues, allowing for substantial functional plasticity. Importantly, a subset of IL-17/IFNγ double-producing Th17 cells was identified in both human and mouse models. Evidence is accumulating that these IL-17/IFNγ double-producing cells are pathogenic drivers in autoimmune diseases, including rheumatoid arthritis, multiple sclerosis and inflammatory bowel disease. In addition, IL-17/IFNγ double-producing cells have been identified in disorders in which the role of autoimmunity remains unclear, such as sarcoidosis. The observed plasticity of Th17 cells towards the Th1 phenotype can be explained by extensive epigenetic priming of the IFNG locus in Th17 cells. In fact, Th17 cells display an IFNG chromatin landscape that is remarkably similar to that of Th1 cells. On the other hand, pathogenic capabilities of Th17 cells can be restrained by stimulating IL-10 production and transdifferentiation into IL-10 producing T regulatory type 1 (Tr1) cells. In this review, we discuss recent advances in our knowledge on the cellular and molecular mechanisms involved in Th17 differentiation, heterogeneity and plasticity. We focus on transcriptional regulation of the Th17 expression program, the epigenetic dynamics involved, and how genetic variants associated with autoimmunity may affect immune responses through distal gene regulatory elements. Finally, the implications of Th17 cell plasticity for the pathogenesis and treatment of human autoimmune diseases will be discussed.