Th17 plasticity and its changes associated with inflammatory bowel disease

Abstract

CD4 T helper (Th) cell differentiation into distinct T cell subsets is critical to the normal function of the immune system. Until recently, the paradigm held that naïve T cells differentiated into distinct subsets under the guidance of environmental cues (e.g., cytokines) and that once polarized, these cells were committed to a particular functional state. However, the existence of transdifferentiated T cell populations, which express signature transcription factors and cytokines associated with more than one Th subset, challenges the immutability of T helper subsets and suggests that plasticity is a feature of multifaceted immune responses. How this process impacts immune dysregulation in diseases such as inflammatory bowel diseases (IBD) and the machinery that underlies this process is far from fully understood. Interleukin (IL)-17 secreting helper T (Th17) cells have been heavily implicated in tissue-specific immune pathology including murine models of IBD, human Crohn's disease and ulcerative colitis. Plasticity within this subset is suggested by the existence of IL-17 secreting cells, which, can also secrete interferon-γ, the signature cytokine for Th1 cells or, can co-express the anti-inflammatory transcription factor forkhead box p3, a signature transcription factor of regulatory T cells. In this review we mainly discuss evidence for Th17 plasticity, mechanisms, which govern it, and highlight the potential to therapeutically target this process in human IBD.

Keywords: Inflammatory bowel disease; Regulatory T cells; T cell plasticity; Th7.

Figure 1

Concept of 17 secreting helper T plasticity. The Foxp3 expressing Treg subset either develops naturally (nTreg) or is peripherally induced from naïve T cells (iTreg). Th17 generating factors including cytokines, transcription factors, and other molecular cues can induce these cells to differentiate into transitional cells with co-expression of Foxp3 and RORc. Th17 cells may be converted into Th17/1-transitional cells with co-expression of RORc and TBX21. Th17: 17 secreting helper T; Foxp3: Forkhead box p3; RORγt: Related orphan receptor γ thymus in mouse; IL: Interleukin; TGF: Transforming growth factor; IFN: Interferon.

Figure 2

Factors influencing the plasticity between Treg and 17 secreting helper T subsets. Cytokines and growth factors (shown in blue letters) may trigger transdifferentiation of the pre-committed Foxp3 expressing Treg population to RORc expressing cells. Micro RNAs (miR, shown in red letters) play a pivotal role in differentially regulating Treg/Th17 plasticity. Transcription factors (aqua ovals) direct the plasticity by positively or negatively controlling Foxp3 and/or RORc expression. The aryl hydrocarbon receptor (AhR, green circle) can promote distinct differentiation pathways in response to two pathway-specific ligands (TCDD and FICZ, Green circles) resulting in either augmentation of Foxp3 or RORc, respectively. Th17: 17 secreting helper T; FICZ: 6-formylindolo [3,2-b] carbazole; TCDD: Tetrachlorodibenzo-p-dioxin; FICZ: Formylindolo [3,2-b] carbazole; AhR: Aryl hydrocarbon receptor; Treg: Regulatory T cells.