Cytokines and transcription factors in the differentiation of CD4+ T helper cell subsets and induction of tissue inflammation and autoimmunity

Abstract

CD4⁺T helper (Th) cells are critical in homeostasis and host defense but are also central to the development of various autoimmune diseases if they become dysregulated. Specifically, pathogenic Th1 and Th17 cells contribute to autoimmune inflammation whereas Treg and Tr1 cells are important for maintaining immune tolerance and resolution of inflammation, respectively. Cytokines trigger signaling pathways in naive T cells that induce lineage-defining transcription factors that direct their differentiation into the distinct T helper cell subsets. It has become clear that the differentiation of T helper cells is not only influenced by the cytokine milieu but also by their metabolic state, cues from the microbiota and the tissue they reside in. A comprehensive understanding how these various stimuli contribute to T helper cell differentiation and phenotype could potentially provide novel ways for therapeutic intervention in autoimmunity and tissue inflammation.

Figure 1.

Overview of Th1, Th17, Treg and Tr1 cell subsets. Cytokines that are critical to their differentiation are highlighted in bold. For Th17 cells, three alternative differentiation conditions are shown. Additional important cytokines contributing to the four subsets are listed in parentheses. Critical genes for each lineage that are actively expressed are highlighted as small promoter symbols with an arrow within the nucleus. In certain instances, protein complexes are highlighted specifically bound to such promoters. Effector cytokines are indicated in bold: IFN-γ and GM-CSF for Th1 cells; IL-17, IL-22 and GM-CSF for Th17 cells; IL-10 for both Tregs and Tr1 cells. IL-2 has been shown to support the Th1 cell lineage whereas it inhibits Th17 cell differentiation. An important aspect of Treg cell function is limiting bio-available IL-2 by expression of IL-2Rα (CD25). The critical importance of IL-23 signaling to the function of Th17 cells is emphasized by depiction of the functional receptor for IL-23 consisting of IL-12Rβ1 and IL-23R. In many instances, master transcription factors suppress the expression of genes important for other T helper cell subsets. This notion is exemplified for Tregs through collaborative repression of genes by Eos and FoxP3 but is an important mechanism of master transcription factors of all lineages so far with the exception of Tr1 cells for which no master transcription factor has been identified yet. The genes encoding the master transcription factors of Th1, Th17 and Treg cells are shown in red, respectively (Tbx21, Rorc and Foxp3). JAK/STAT signaling pathways have particular relevance to T helper cell differentiation as they mediate the instructive signals of the lineage inducing cytokines: STAT1/4 relevant for Th1 cells and STAT3 for Th17 cells, respectively. The critical contribution of TCR signaling for differentiation of T helper cell subsets has been omitted for clarity.

Figure 2.

(A) Mitochondrial metabolism is critical to Th1 cell differentiation and terminal effector function. The malate-aspartate shuttle and mitochondrial citrate export drive proliferation and their activity is translated mechanistically through epigenetic changes influencing the transcription of key Th1 cell genes. The TCA (tricarboxylic acid) cycle is critical to terminal effector function of Th1 cells. (B) Metabolites such as bile acids and their derivatives which are generated through processing by the microbiome are important regulators of Th17 cell differentiation, e.g. 3-oxoLCA can directly bind to the Th17 cell master transcription factor RORγt and inhibit transcription of Il17. In contrast, the bile acid metabolite isoalloLCA can lead to the expansion of Tregs thereby contributing to tolerance. (C) Tregs have been shown to possess very important tissue-resident functions such as the repair of damaged tissue. Indeed, Tregs can secrete oligodendrogenic Ccn3 to enhance oligodendrogenesis in the setting of CNS demyelination. (D) Model showing the interconnected relationship among the pro-inflammatory Th1/Th17 cell subsets and the regulatory Treg/Tr1 cell subsets. The biological outcome of either inflammation/autoimmunity or tolerance/resolution of inflammation is dictated by the expansion and dominance of either pro-inflammatory or regulatory Th cell subsets. T helper cell differentiation and expansion occurs under the influence of a complex network of mechanisms. These mechanisms can dynamically shift the balance between pro-inflammatory and regulatory subsets suggested as cogwheels tipping the balance in a particular direction. For example, metabolites generated or processed by the microbiome can foster Treg cell differentiation. The inherent plasticity of Th17 cells can lead to their transdifferentiation to either Tregs or Tr1 cells. T helper cell differentiation and effector function is critically influenced by the tissue immunological milieu and the interplay with other immune cells.