The role of transforming growth factor <i>β</i> in T helper 17 differentiation

<jats:title>Summary</jats:title><jats:p>T helper 17 (Th17) cells play critical roles in inflammatory and autoimmune diseases. The lineage‐specific transcription factor <jats:styled-content style="fixed-case">ROR</jats:styled-content><jats:italic>γ</jats:italic>t is the key regulator for Th17 cell fate commitment. A substantial number of studies have established the importance of transforming growth factor <jats:italic>β</jats:italic> (<jats:styled-content style="fixed-case">TGF</jats:styled-content>‐<jats:italic>β</jats:italic>) ‐dependent pathways in inducing <jats:styled-content style="fixed-case">ROR</jats:styled-content><jats:italic>γ</jats:italic>t expression and Th17 differentiation. <jats:styled-content style="fixed-case">TGF</jats:styled-content>‐<jats:italic>β</jats:italic> superfamily members <jats:styled-content style="fixed-case">TGF</jats:styled-content>‐<jats:italic>β</jats:italic><jats:sub>1</jats:sub>, <jats:styled-content style="fixed-case">TGF</jats:styled-content>‐<jats:italic>β</jats:italic><jats:sub>3</jats:sub> or activin A, in concert with interleukin‐6 or interleukin‐21, differentiate naive T cells into Th17 cells. Alternatively, Th17 differentiation can occur through <jats:styled-content style="fixed-case">TGF</jats:styled-content>‐<jats:italic>β</jats:italic>‐independent pathways. However, the mechanism of how <jats:styled-content style="fixed-case">TGF</jats:styled-content>‐<jats:italic>β</jats:italic>‐dependent and <jats:styled-content style="fixed-case">TGF</jats:styled-content>‐<jats:italic>β</jats:italic>‐independent pathways control Th17 differentiation remains controversial. This review focuses on the perplexing role of <jats:styled-content style="fixed-case">TGF</jats:styled-content>‐<jats:italic>β</jats:italic> in Th17 differentiation, depicts the requirement of <jats:styled-content style="fixed-case">TGF</jats:styled-content>‐<jats:italic>β</jats:italic> for Th17 development, and underscores the multiple mechanisms underlying <jats:styled-content style="fixed-case">TGF</jats:styled-content>‐<jats:italic>β</jats:italic>‐promoted Th17 generation, pathogenicity and plasticity. With new insights and comprehension from recent findings, this review specifically tackles the involvement of the canonical <jats:styled-content style="fixed-case">TGF</jats:styled-content>‐<jats:italic>β</jats:italic> signalling components, <jats:styled-content style="fixed-case">SMAD</jats:styled-content>2, <jats:styled-content style="fixed-case">SMAD</jats:styled-content>3 and <jats:styled-content style="fixed-case">SMAD</jats:styled-content>4, summarizes diverse <jats:styled-content style="fixed-case">SMAD</jats:styled-content>‐independent mechanisms, and highlights the importance of <jats:styled-content style="fixed-case">TGF</jats:styled-content>‐<jats:italic>β</jats:italic> 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 <jats:styled-content style="fixed-case">TGF</jats:styled-content>‐<jats:italic>β</jats:italic> in Th17 generation and function.</jats:p>