The Th17 subset is primarily involved in recruiting neutrophils and, to a lesser extent, monocytes to sites of infection and inflammation, and in maintaining the integrity of epithelial barriers. These actions are critical for destroying bacteria and fungi, microbes that are killed by the phagocytes, and repairing injured epithelial layers, but they also contribute significantly to chronic inflammatory diseases.
Development of Th17 Cells
The development of Th17 cells is stimulated by proinflammatory cytokines produced in response to bacteria and fungi (Fig. 1). Various bacteria and fungi act on DCs and macrophages and stimulate the production of cytokines, including IL-6, IL-1, and IL-23, all of which promote differentiation of CD4+ T cells to the Th17 subset. Engagement of the lectin Dectin-1 on dendritic cells by fungal glucans is a signal for the production of these cytokines. Whereas IL-6 and IL-1 stimulate the early steps in Th17 differentiation, IL-23 may be more important for the proliferation and maintenance of differentiated Th17 cells. A surprising aspect of Th17 differentiation is that TGF-β, which is produced by many cell types and is an anti-inflammatory cytokine, promotes the development of proinflammatory Th17 cells when other mediators of inflammation, such as IL-6 or IL-1, are present. Th17 differentiation is inhibited by IFN-γ and IL-4; therefore, strong Th1 and Th2 responses tend to suppress Th17 development.
Fig1. Differentiation of Th17 cells. Interleukin-6 (IL-6) and IL-1 produced by antigen-presenting cells (APCs) and transforming growth factor–β (TGF-β) produced by various cells activate the transcription factors RORγt and STAT3, which stimulate the differentiation of naive CD4+ T cells to the Th17 subset. IL-23, which is also produced by APCs, especially in response to fungi, promotes proliferation of the differentiating Th17 cells. TGF-β may promote Th17 responses indirectly by sup pressing Th1 and Th2 cells, both of which inhibit Th17 differentiation (not shown). IL-21 produced by the Th17 cells amplifies this response.
The development of Th17 cells is dependent on the transcription factors RORγt and STAT3 (see Fig. 1). TGF-β and the inflammatory cytokines, mainly IL-6 and IL-1, work cooperatively to induce the production of RORγt, a transcription factor that is a member of the retinoic acid receptor family. RORγt is a T cell–restricted protein encoded by the RORC gene, so sometimes the protein may be called RORc. Inflammatory cytokines, notably IL-6, activate the transcription factor STAT3, which functions with RORγt to drive the Th17 response.
Th17 cells are abundant in mucosal tissues, particularly of the gastrointestinal tract, suggesting that the tissue environment influences the differentiation and maintenance of this subset, perhaps by providing high local concentrations of TGF-β and inflammatory cytokines. This observation also suggests that Th17 cells may be especially important in combating intestinal infections and in the development of pathologic intestinal inflammation. The development of Th17 cells in the gastrointestinal tract is dependent on the gut microbiome; in mice, commensal bacteria related to Clostridium species are potent inducers of Th17 cells.
Functions of Th17 Cells
Th17 cells combat microbes by recruiting leukocytes, mainly neutrophils, to sites of infection (Fig. 2). Phagocytosis by neutrophils is a major defense mechanism against many common bacteria and fungi that can survive outside cells but are killed in the phagolysosomes of neutrophils. Th17 cells play an important role in defense against these infections by bringing neutrophils to the microbes. Most of the functions of Th17 cells in host defense are mediated by IL-17, but other cytokines produced by this subset may also contribute.
Fig2. Functions of Th17 cells. Cytokines produced by Th17 cells stimulate local production of chemokines that recruit neutrophils and other leukocytes, increase production of antimicrobial peptides (defensins), and promote epithelial barrier functions. APC, Antigen-presenting cell; CSF, colony-stimulating factor; IL, interleukin; TNF, tumor necrosis factor.
Interleukin-17
IL-17 is an unusual cytokine because neither it nor its receptor is homologous to any other known cytokine-receptor pair. The IL-17 family includes six structurally related proteins, of which IL-17A and IL-17F are the most similar, and the immunologic functions of this cytokine family are mediated primarily by IL-17A. IL-17A is produced by Th17 cells as well as ILC3s and some γδ and CD8+ T cells. IL-17 receptors are multimeric and expressed on a wide range of cells. They activate NF-κB and other transcription factors.
IL-17 is an important link between T cell–mediated adaptive immunity and the acute inflammatory response, which we discussed in Chapter 4 as one of the major reactions of innate immunity. When Th17 cells are activated, these reactions are greater in magnitude and more prolonged than what is seen in innate immunity when T cells are not involved. IL-17 has several important functions in host defense.
• IL-17 induces neutrophil-rich inflammation. It stimulates the production of chemokines, such as IL-8, and other cytokines, such as TNF, that recruit neutrophils and, to a lesser extent, monocytes to the site of T-cell activation. IL-17 also enhances neutrophil generation by increasing the production of granulocyte colony-stimulating factor (G-CSF) and the expression of its receptors. Recruited neutrophils ingest and destroy bacteria and fungi.
• IL-17 stimulates the production of antimicrobial sub stances, including defensins, from numerous cell types.
Other Th17 Cytokines
IL-22 is a member of the type II cytokine family. It is produced by activated T cells, particularly Th17 cells, and by some NK cells and ILCs. The IL-22 receptor is a heterodimer in which one of the chains is also a component of the IL-10 receptor. It signals via JAK1, TYK2, and STAT3. IL-22 is produced by Th17 cells in epithelial tissues, especially of the skin and gastrointestinal tract, and serves to maintain epithelial integrity, mainly by promoting the barrier function of epithelia, by stimulating repair reactions, and by inducing the production of antimicrobial peptides. IL-22 also contributes to inflammation, in part by stimulating epithelial production of chemokines, and may therefore be involved in tissue injury in inflammatory diseases.
Roles of Th17 Cells in Host Defense
The principal function of Th17 cells is to recruit leukocytes that destroy extracellular bacteria and fungi (see Fig. 2). The neutrophils that are recruited by Th17 cells ingest and kill extracellular microbes. The importance of this role of Th17 cells is illustrated by the inherited disease called or hyper-IgE syndrome (Job syndrome), which is caused by dominant negative mutations in STAT3 resulting in defective Th17 development, and is characterized by increased susceptibility to cutaneous fungal and bacterial infections and allergic disorders. Defective Th17 function is also associated with chronic mucocutaneous candidiasis. Patients with the autoimmune polyglandular syndrome produce autoantibodies against their own IL-17 and also develop candidiasis.
Th17 cells contribute to the pathogenesis of many inflammatory diseases. Th17 responses have been associated with psoriasis, inflammatory bowel disease, rheumatoid arthritis, and multiple sclerosis. Agents that block the development or functions of Th17 cells are very effective for the treatment of psoriasis and are being tested in other diseases. These antagonists are not beneficial in Crohn’s disease, an inflammatory bowel disease, so despite the abundance of Th17 cells in the intestines, the role of these cells in Crohn’s disease is uncertain. In some chronic inflammatory diseases, both IL-17 and IFN-γ contribute to the disease. These two cytokines may be produced by a subset of Th17 cells that are thought to be highly pathogenic or by a mixture of Th17 and Th1 cells in the lesions.
Th17 cells help to maintain the integrity of epithelial barriers, such as in the intestinal tract. This function is partly because these T cells limit the entry of infectious microbes through the barriers by stimulating local production of antimicrobial peptides and partly because IL-22 promotes the regeneration of epithelia. It is possible that different populations of Th17 cells are involved in this protective function and in the pathologic reactions caused by this subset.
