Th 17 cells interplay with Foxp3+ Tregs in regulation of inflammation and autoimmunity

Abstract

T helper 17 cells (Th17) are a new CD4+ T helper subset that has been implicated in inflammatory and autoimmune diseases. Th17, along with CD4(+)CD25(high) Foxp3(+) regulatory T cells (Tregs) and other new T helper subsets, have expanded the Th1-Th2 paradigm. Although this new eight-subset paradigm significantly improved our understanding on the differentiation and regulation of CD4+ T helper subsets, many questions remain to be answered. Here we will briefly review the following issues: a) Old Th1-Th2 paradigm versus new multi-subset paradigm; b) Structural features of IL-17 family cytokines; c) Th17 cells; d) Effects of IL-17 on various cell types and tissues; e) IL-17 receptor and signaling pathways; f) Th17-mediated inflammations; and g) Protective mechanisms of IL-17 in infections. Lastly, we will examine the interactions of Th17 and Treg in autoimmune diseases and inflammation: Th17 cells interplay with Tregs. Regulation of autoimmunity and inflammation lies in the interplays of the different T helper subsets, therefore, better understanding of these subsets' interactions would greatly improve our approaches in developing therapy to combat inflammatory and autoimmune diseases.

Figure 1

Th17 Cell Differentiation. Upon activation by antigen presenting cells, naïve T helper cells can differentiate into different T helper subsets. In the presence of TGF-β and pro-inflammatory cytokines such as IL-6, IL-23, or IL-1β, naïve T cell differentiates into Th17 cells. The differentiation of Th17 is inhibited by hallmark cytokines of other T helper subsets. Pro-inflammatory cytokines can induce further effector molecules in committed Th17 cells to establish their terminally differentiated effector phenotype.

Figure 2

IL-17 Cytokine-Receptor Relationships. The IL-17 cytokine family has six members, IL-17A, IL-17B, IL-17C, IL-17D, IL-17E and IL-17F. The IL-17 receptor family is made of five distinct receptors, IL-17RA, IL-17RB, IL-17RC, IL-17RD and IL-17RE. The IL-17 receptor complexes through which IL-17 cytokines induce signaling are shown. The exact stoichiometry of each IL-17 receptor complex has not been completely elucidated. Ligands for the IL-17RD or IL-17RA-IL-17RD complex are yet to be identified. The receptor through which IL-17D induces signaling needs to be verified.

Figure 3

Main Structural Features of IL-17 Receptor and IL-17 Signaling Pathways. Extracellular domain of the IL-17 receptor has two fibronectin III-like domains (FN), which mediate ligand binding. Intracellular domain of IL-17 receptor contains a SEFIR domain, which defines IL-17 receptors as members of the “similar expression to fibroblast growth factor genes, IL-17 receptors and Toll-like receptors-IL-1R” (SEFIR) family. A TIR-like loop (TILL) and a C/EBPβ-activation domain (CBAD) are found in IL-17RA intracellular domain. ACT1 is a critical adaptor protein in IL-17 signaling pathways. ACT1 associates with TRAF6, TRAF3 and TAK1 in mediating signals downstream of IL-17 receptor. IL-17 receptor pathways activates NF-κB, MAPK, C/EBPβ and C/EBPδ, which lead to target gene transcriptions of pro-inflammatory chemokines and cytokines.

Figure 4

Interplay between Tregs and Th17 Lineages. Differentiation of CD4⁺ T Cell is important for immune regulation and host defense. Signaling pathways in Tregs and Th17 differentiation show specific cytokines, receptors, and transcription factors involved in each lineage. TGF-β is a common factor in the differentiation of two lineages with opposing effects. Effector cytokines of Tregs enhance anti-inflammatory/immunosuppressive effects and thus inhibit inflammation and autoimmune reactions. Effector cytokines of Th17 are pro-inflammatory and enhance inflammation and autoimmune reactions.