Posttranscriptional regulation of T helper cell fate decisions

Abstract

T helper cell subsets orchestrate context- and pathogen-specific responses of the immune system. They mostly do so by secreting specific cytokines that attract or induce activation and differentiation of other immune or nonimmune cells. The differentiation of T helper 1 (Th1), Th2, T follicular helper, Th17, and induced regulatory T cell subsets from naive T cells depends on the activation of intracellular signal transduction cascades. These cascades originate from T cell receptor and costimulatory receptor engagement and also receive critical input from cytokine receptors that sample the cytokine milieu within secondary lymphoid organs. Signal transduction then leads to the expression of subset-specifying transcription factors that, in concert with other transcription factors, up-regulate downstream signature genes. Although regulation of transcription is important, recent research has shown that posttranscriptional and posttranslational regulation can critically shape or even determine the outcome of Th cell differentiation. In this review, we describe how specific microRNAs, long noncoding RNAs, RNA-binding proteins, and ubiquitin-modifying enzymes regulate their targets to skew cell fate decisions.

Figure 1.

Regulatory processes during Th1 differentiation. Noncoding RNAs, RBPs, and E3 ligases/DUBs are shown in blue, red, and green, respectively. For clarity of depiction, these posttranscriptional regulators were not necessarily placed at the correct cellular site of activity. Dashed lines indicate an indirect effect. Molecular interactions are explained in the text.

Figure 2.

Regulatory processes during Th2 differentiation. Noncoding RNAs, RBPs, and E3 ligases/DUBs are shown in blue, red, and green, respectively. For clarity of depiction, these posttranscriptional regulators were not necessarily placed at the correct cellular site of activity. Molecular interactions are explained in the text.

Figure 3.

Regulatory processes during Tfh differentiation. Noncoding RNAs, RBPs, and E3 ligases/DUBs are shown in blue, red, and green, respectively. For clarity of depiction, these posttranscriptional regulators were not necessarily placed at the correct cellular site of activity. Dashed lines indicate indirect effects. Molecular interactions are explained in the text.

Figure 4.

Regulatory processes during Th17 differentiation. Noncoding RNAs, RBPs, and E3 ligases/DUBs are shown in blue, red, and green, respectively. For clarity of depiction, these posttranscriptional regulators were not necessarily placed at the correct cellular site of activity. Dashed lines indicate a suspected effect. Molecular interactions are explained in the text.

Figure 5.

Regulatory processes during iTreg cell differentiation. Noncoding RNAs, RBPs, and E3 ligases/DUBs are shown in blue, red, and green, respectively. For clarity of depiction, these posttranscriptional regulators were not necessarily placed at the correct cellular site of activity. Dashed lines indicate an indirect effect. Molecular interactions are explained in the text.