Transcriptional regulatory networks in Th17 cell differentiation

Abstract

Upon encountering antigen in the context of antigen presenting cells, naïve CD4(+) T cells undergo differentiation into effector T helper (Th) cells, which can secrete high levels of cytokines and other immunomodulators to mediate host defense and tissue inflammation. During the past three years, the immunology field has witnessed an explosion of research advances in the biology of Th17 cells, the most recently described subset of T helper cells, which play crucial roles in host immunity and inflammation. Here we review emerging data on transcriptional regulatory networks that govern the differentiation program of Th17 cells, and focus on how the orphan nuclear receptor RORgammat coordinates this process in concert with diverse cytokine-induced transcription factors.

Figure 1. TGF-β orchestrates in vitro Th17 and Treg cell differentiation in a concentration-dependent manner

In the presence of TGF-β, TCR-activated CD4⁺ T cells express both RORγt and Foxp3, but RORγt function is antagonized by Foxp3. Such cells can differentiate into either Th17 or Treg cells dependent on the cytokine environment. In the presence of proinflammatory cytokines and low concentrations of TGF-β, RORγt expression is further upregulated, whereas Foxp3 expression and function are inhibited, thus tipping the balance in favor of the Th17 cell fate. RORγt-induced IL-23R expression on T cells confers responsiveness to IL-23, which further promotes Th17 cell differentiation. In contrast, in the absence of proinflammatory cytokines, high concentrations of TGF-β favor Foxp3 expression and result in Treg cell differentiation.

Figure 2. Transcriptional regulatory network that governs the Th17 cell differentiation program

The inflammatory cytokine (IL-6)-initiated signaling cascade, together with TGF-β signaling, induces RORγt expression in a Stat3-dependent manner. In the absence of proinflammatory cytokines, TGF-β-induced Foxp3 inhibits RORγt (and RORα) activity, and thus promotes Treg cell differentiation. AhR is also induced during Th17 cell polarization and it downregulates Foxp3 expression. Ligand activated AhR cooperates with RORγt to induce maximal amounts of IL-17 and IL-22 and also to inhibit TGF-β-induced Foxp3 expression, ensuring full progression of Th17 cell differentiation. TCR-induced IRF-4 upregulates RORγt expression and inhibits Foxp3 expression, and thus promotes Th17 cell differentiation and antagonizes Treg cell differentiation. TCR-activated IBP inhibits IRF-4 function by sequestering IRF-4. TCR-induced Runx1 influences Th17 cell differentiation by inducing RORγt expression and by binding to and acting together with RORγt to direct il17 transcription.