Molecular mechanisms underpinning T helper 17 cell heterogeneity and functions in rheumatoid arthritis

T helper 17 (Th17) cells are important mediators of immune responses against extracellular bacteria and fungi, and as such play critical regulatory roles in maintaining mucosal homeostasis. Conversely, Th17 cells and their effector molecules interleukin 17A (IL-17A), IL-17F, interferon (IFN)γ, tumor necrosis factor (TNF)α, and granulocyte-macrophage colony-stimulating factor (GM-CSF) are implicated in the pathology of rheumatoid arthritis (RA). Interactions between Th17 cells and other immune cells or stromal cells that are present in the synovial tissue during the earliest phases of the disease, may eventually lead to chronic inflammation, irreversible cartilage degradation and bone erosions. Recent evidence points towards Th17 cell plasticity as an essential contributing process in RA pathology, since Th17 cells are able to adopt a pathogenic phenotype under the influence of environmental, inflammatory and genetic factors. A remarkable feature of this pathogenic Th17 cell phenotype is the high production of GM-CSF and TNFα and the co-appearance of Th1 cell characteristics, such as transcription factor T-box 21 (T-bet) and IFNγ expression. Recently, much progress has been made in unravelling the mechanisms underlying Th17 cell plasticity and pathogenicity. Of interest, many of the environmental and inflammatory factors associated with RA pathology, such as pro-inflammatory mediators and cytokines, microbiome dysbiosis, metabolism and diet, obesity, vitamins, steroids and hormones are linked to the development of pathogenic Th17 cells. Moreover proteins encoded by established genetic risk factors for RA including CCR6, CD226, CSF2, EOMES, ETS1, GATA3, IL2, IL6R, IL23R, IKZF3, IRAK1, IRF4, IRF8, PRKCQ, PRDM1, RBPJ, RUNX1 and TAGAP are directly involved in Th17 cell differentiation and/or function. This review provides a detailed overview of the molecular mechanisms involved in the heterogeneity and pathogenicity of Th17 cells in the context of autoimmune diseases, with a focus on RA. Understanding these mechanisms creates great potential to identify and select novel therapeutic targets which could improve current therapies or lead to development of new treatment strategies in RA.