The role of transforming growth factor β in T helper 17 differentiation

Abstract

T helper 17 (Th17) cells play critical roles in inflammatory and autoimmune diseases. The lineage-specific transcription factor RORγt is the key regulator for Th17 cell fate commitment. A substantial number of studies have established the importance of transforming growth factor β (TGF-β) -dependent pathways in inducing RORγt expression and Th17 differentiation. TGF-β superfamily members TGF-β₁ , TGF-β₃ or activin A, in concert with interleukin-6 or interleukin-21, differentiate naive T cells into Th17 cells. Alternatively, Th17 differentiation can occur through TGF-β-independent pathways. However, the mechanism of how TGF-β-dependent and TGF-β-independent pathways control Th17 differentiation remains controversial. This review focuses on the perplexing role of TGF-β in Th17 differentiation, depicts the requirement of TGF-β for Th17 development, and underscores the multiple mechanisms underlying TGF-β-promoted Th17 generation, pathogenicity and plasticity. With new insights and comprehension from recent findings, this review specifically tackles the involvement of the canonical TGF-β signalling components, SMAD2, SMAD3 and SMAD4, summarizes diverse SMAD-independent mechanisms, and highlights the importance of TGF-β signalling in balancing the reciprocal conversion of Th17 and regulatory T cells. Finally, this review includes discussions and perspectives and raises important mechanistic questions about the role of TGF-β in Th17 generation and function.

Keywords: SMAD; T helper 17 differentiation; transforming growth factor β.

Figure 1

T helper 17 (Th17) differentiation. Interleukin‐6 (IL‐6) or IL‐21 activates signal transducer and activator of transcription 3 (STAT3) to potentiate Rorc expression, which encodes the retinoic‐acid‐receptor‐related orphan nuclear receptor γt (ROR γt) transcription factor. IL‐6 activates STAT3 through classic, trans or cluster signalling pathways. Additional transforming growth factor‐β (TGF‐β) or activin A degrades SKI to reverse the SKI/SMAD4 complex imposed repression on Rorc transcription. Unleashed ROR γt binds to the Il17a, Il17f loci and drives T cells to produces Th17 cytokines, e.g. IL‐17A, IL‐17F, IL‐21 and TGF‐β. Dendritic cells produce multiple cytokines to promote Th17 differentiation, such as IL‐6, IL1‐β, IL‐23 and activin A. Dendritic cells also express integrin α _v/β ₈ to process the latent form of TGF‐β to the active form.

Figure 2

Transforming growth factor‐β (TGF‐β) promotes T helper 17 (Th17) differentiation through multiple mechanisms. Signal transducer and activator of transcription 3 (STAT3), induced by interleukin‐6 (IL‐6) or IL‐21, potentiates the Th17‐related transcriptional programme by binding to Rorc, Il17a, and Il21 loci. TGF‐β receptor signalling phosphorylates SMAD2 and SMAD3. The SMAD2/3 complex interacts with SMAD4 and translocates into the nucleus. Meanwhile, SMAD2 and SMAD3 act as a co‐activator and co‐repressor of STAT3, and oppositely modify STAT3‐induced transcription. TGF‐β signalling triggers SKI degradation to unleash SMAD4 and SKI complex repressed ROR γt expression. TGF‐β suppresses SOCS3 to prolong STAT3 activation. TGF‐β suppresses GFI‐1 to promote Il17a transcription. TGF‐β suppresses Eomes through the JNK‐c–JUN pathway to enhance Rorc and Il17a transcription. TGF‐β drives RhoA‐ROCK2 to phosphorylate IRF4 and to up‐regulate the expression of ROR γt, IL‐17 and IL‐21. TGF‐β induces TAZ to co‐activate ROR γt and to reduce Foxp3 through proteasomal degradation.

Figure 3

T helper differentiation. Diagram of T helper differentiation pathways for T helper 1 (Th1), Th2, Th9, Th17, Th22, regulatory T (Treg), regulatory T type 1 (Tr1) and T follicular helper (Tfh) cells. Cytokines that play an important role in inducing CD4⁺ T‐cell differentiation are listed above the cell types, and cell‐specific transcription factors are listed in a box below the cell types.