The role of transforming growth factor in T helper 17 differentiation

T helper 17 (Th17) cells play critical roles in inflammatory and autoimmune diseases. The lineage-specific transcription factor RORt is the key regulator for Th17 cell fate commitment. A substantial number of studies have established the importance of transforming growth factor (TGF-) -dependent pathways in inducing RORt expression and Th17 differentiation. TGF- superfamily members TGF-(1), TGF-(3) 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--independent pathways. However, the mechanism of how TGF--dependent and TGF--independent pathways control Th17 differentiation remains controversial. This review focuses on the perplexing role of TGF- in Th17 differentiation, depicts the requirement of TGF- for Th17 development, and underscores the multiple mechanisms underlying TGF--promoted Th17 generation, pathogenicity and plasticity. With new insights and comprehension from recent findings, this review specifically tackles the involvement of the canonical TGF- signalling components, SMAD2, SMAD3 and SMAD4, summarizes diverse SMAD-independent mechanisms, and highlights the importance of TGF- 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- in Th17 generation and function.