Recently a new lineage of CD4+T cells, type 17 helper T (Th17)cells producing the signature cytokines interleukin (IL)-17, IL-21,and IL-22, has been identified. This has fundamentally changed the Th1/Th2 dichotomy paradigm. The Th1 cell subset is characterized by interferon (IFN)-γ production and T-bet expression, whereas the Th2 cell lineage shows IL-4, IL-5, and IL-10 productionand GATA-3 expression. At the other extreme, Treg cells expressing FoxP3 are essential to maintain the homeostasis of cell subsets involved in adaptive immunity by contact-dependent suppressionor by releasing anti-inflammatory cytokines, IL-10 and transforming growth factor (TGF)-β1.
Like Th1, Th2, and Treg cells, specific polarizing cytokines—TGF-β, IL-6, and IL-23—are required for differentiation of Th17 cells which express the transcription factors retinoic acid orphan receptor (ROR)α and RORγt. However, Th17 cells do not represent a homogeneous lineage, as they can be reprogrammed to other T-cell subsets depending on the cytokine environment. Accordingly, IL-17 can be co-expressed with a variety of other cytokines including IFN-γ,IL-10,andIL-4.Indeed,a mixed Th1 –Th17 subgroup expressing both T-bet and RORγt has been recently identified in the setting of autoimmunity. Plasticity between Th17 and Treg cells has also been observed. In humans,IL-17-producing ROR γt+FoxP3+ T cells that retain their ability to suppress effector lymphocytes have been described (Figure 1). As a consequence of these recent acquisitions, it is now clear that Th17 cells produce cytokines that mediate immune responses that are both good and bad.
Th17 cells represent a new lineage distinct from Th1 and Th2 cells. In murine models, Th17 cells have been shown to have either a pathogenic or protective role in diseases such as experimental autoimmune encephalomyelitis (EAE) or autoimmune uveitis (EAU). Through their expression of the transcription factor RORγt, Th17 cells play critical roles in the development of autoimmunity and allergic reactions by producing IL-17 and, to a lesser extent, TNF-α and IL-6.
The IL-17 cytokine family consists of six members, IL-17 (also called IL-17A), IL-17B, IL-17C, IL-17D, IL-17E (also called IL-25), and IL-17F. And its receptor (IL17R) family contains five subunits. IL17RA is ubiquitously expressed throughout the body, resulting in pleiotropic actions of IL-17 on a wide range of cell types. The main cells responsive to IL-17 are epithelial cells, endothelial cells, and fibroblasts and, to a lesser degree, macrophages and dendritic cells. IL-17 has been shown to activate many common downstream signaling pathways, including nuclear factor (NF)- kB, resulting in the expression of genes encoding proinflammatory cytokines [tumour necrosis factor-α (TNF-α), IL-1, IL-6, granulocyte colony-stimulating factor (G-CSF), and granulocyte – macrophage colony-stimulating factor (GM-CSF)], chemokines (CXCL1, CXCL5, IL-8, CCL2, and CCL7), matrix metalloproteinases (MMP1, MMP3, MMP9, and MMP13), and antimicrobial peptides (defensins and S100 proteins). IL-17 also promotes G-CSF-mediated granulopoiesis and recruits neutrophils to the inflammatory sites. These effects attributed to IL-17 might play a role in atherosclerotic plaque formation and complication (Figure 2).
Robust evidence shows that IL-17 mediates adverse effects in rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, inflammatory bowel disease, and psoriasis. IL-17 also plays critical roles in the pathogenesis of other inflammatory diseases such as allergy, transplantation, obesity, and malignancy, as well as protective roles in host defence against infections and in vaccine-induced immunity.