Th17 plasticity and its changes associated with inflammatory bowel disease

Table 1 Cytokines related to 17 secreting helper T development and plasticity in human

Cytokine	Effect	Ref.
IL-1β	Accelerate IL-17A secretion from IL-17 secreting Innate	[69]
	Lymphoid cells and Th17
IL-6	Induce autocrine IL-21 and generation of Th17	[20]
IL-10	Suppress IL-17A and Th17 generation	[62]
IL-12	Induce IFN-γ secretion from Th17 cells (Th1/Th17 plasticity)	[20]
IL-21	Potentiates pathogenic effects of Th17 cells in the gut	[64,65]
IL-22	Attenuate the development of intestinal pathology via Stat3-mediated effects on epithelial cells	[66,67]
IL-23	Induce IL-22 and IL-17A secretions and maintain Th17 expansion	[68]
TGF-β1	Initiate generation of Treg and Th17 populations dependent on the concentration	[63]

Th17: 17 secreting helper T; IL: Interleukin; TGF: Transforming growth factor; IFN: Interferon.

Table 2 Transcription factors related to 17 secreting helper T development and plasticity

Transcription factor	Effect	Ref.
Fosl2	A key determinant of cellular plasticity	[30]
IRF4	Th17 differentiation via RORγt dependent and independent pathways	[115]
	Augmented in patients with IBD and correlated with enhanced production of IL-17 and IL-22 mRNA	[70]
BATF	Required for differentiation of Th17 via induction of RORγt, and bound to IL-17, IL-21 and IL-22 promoters	[116]
	BATF+ RORc- Th17 cells are found in gut tissues from UC but not CD patients.	[73]
HIF-1	A key transregulator of Th17 polarization and suppressor of Foxp3 in Treg	[33,81]
	Reciprocal regulation between HIF-1 and miR210	[81]
Jmjd3	H3K27 demethylase, important for Th1/Th17 plasticity	[101]
RORc (human)	Essential for Th17 differentiation induced by TGF-β1 and IL-6 or IL-21	[35]
RORγt (mouse)
IKZF3 (Aiolos)	Promotes Th17 differentiation via silencing of the IL-2 locus	[74]
	Aiolos+ iTreg respond to IL-1β and downregulate their suppressor functions	[75]

RORγt: Related orphan receptor γ thymus in mouse; IL: Interleukin; TGF: Transforming growth factor; CD: Crohn's disease; UC: Ulcerative colitis; HIF: Hypoxia-inducible factor; IRF4: Interferon regulatory factor 4; IBD: Inflammatory bowel diseases.

Table 3 MicroRNAs influencing 17 secreting helper T development and plasticity

MicroRNA	Inducer	Target	Effect	Ref.
miR10	TGF-β	Bcl-6	Limit Th17, convert Th cells into Treg	[78,83]
miR17-92 cluster		Creb1, TGF-βRII, KZF4 (miR17), PTEN (miR19)	Accumulation of antigen-specific iTreg development, IL-10 production, and possibly Treg cell migration	[78,83]
miR29	NOD2	IL-12p40, IL-23p19	Inhibit IL-23R signalling	[80]
miR126		PIK3R2	Treg-mediated Immunosuppression	[83]
miR132/212 cluster	TCDD, FICZ	Bcl-6	Enhance Th17 development via AhR pathway	[82,83]
miR146a	TLR2-5	STAT1	Block Th1 development	[78,79]
miR155	TLR2-4, TLR9	SOCS1	Unleash STAT1, 4, and 5 signals, and promote Th1, Th2, and Treg	[78,79]
miR210		HIF-1 (counter regulator)	Control Foxp3 expression	[81,83]
miR301		PIAS3	Unleash STAT3 signal, and generate Th17	[78]
miR326		EST-1	Critical for Th17 development	[78]

TGF: Transforming growth factor; Th17: 17 secreting helper T; FICZ: 6-formylindolo [3,2-b] carbazole; TLR: Toll-like receptor; TCDD: Tetrachlorodibenzo-p-dioxin; FICZ: Formylindolo [3,2-b] carbazole.