IL-17 and IL-17-producing cells in protection versus pathology

Abstract

IL-17 cytokine family members have diverse biological functions, promoting protective immunity against many pathogens but also driving inflammatory pathology during infection and autoimmunity. IL-17A and IL-17F are produced by CD4⁺ and CD8⁺ T cells, γδ T cells, and various innate immune cell populations in response to IL-1β and IL-23, and they mediate protective immunity against fungi and bacteria by promoting neutrophil recruitment, antimicrobial peptide production and enhanced barrier function. IL-17-driven inflammation is normally controlled by regulatory T cells and the anti-inflammatory cytokines IL-10, TGFβ and IL-35. However, if dysregulated, IL-17 responses can promote immunopathology in the context of infection or autoimmunity. Moreover, IL-17 has been implicated in the pathogenesis of many other disorders with an inflammatory basis, including cardiovascular and neurological diseases. Consequently, the IL-17 pathway is now a key drug target in many autoimmune and chronic inflammatory disorders; therapeutic monoclonal antibodies targeting IL-17A, both IL-17A and IL-17F, the IL-17 receptor, or IL-23 are highly effective in some of these diseases. However, new approaches are needed to specifically regulate IL-17-mediated immunopathology in chronic inflammation and autoimmunity without compromising protective immunity to infection.

Fig. 1. Drug targets in the IL-23–IL-17 pathway.

Activation of dendritic cells (DCs) and macrophages through pathogen recognition receptors (PRRs) promotes production of IL-23 and IL-1β, which play a major role in the induction and/or expansion of populations of T helper 17 (T_H17) cells, IL-17-secreting γδ T (γδT17) cells and other IL-17-secreting cells (not shown). By contrast IL-12 production by DCs and macrophages promotes development of T_H1 cells. Monoclonal antibodies (mAbs) that neutralize IL-12p40 (ustekinumab) suppress T_H1 cell as well as T_H17 cell and γδT17 cell responses, whereas mAbs that neutralize IL-23 (guselkumab, tildrakizumab and risankizumab) specifically block IL-17-secreting cells. The RORγt transcriptional factor is the master regulator of IL-17 production in diverse cell types and a target for small molecule drugs (SMDs) in development. T_H17 cells, γδT17 cells and other IL-17-secreting cells (not shown) co-produce IL-17A and IL-17F and, while most of the focus has been on mAbs specific for IL-17A (secukinumab and ixekizumab), antibodies that neutralize both IL-17A and IL-17F (bimekizumab) are also in clinical use. These, together with mAbs that bind to IL-17RA (brodalumab) and inhibit binding of IL-17A and IL-17F to IL-17RA–IL-17RC, appear to be marginally more effective than anti-IL-17A mAbs. Finally, peptides, macrocycles and other SMDs that target IL-17R or ACT1 are also in development. GM-CSF, granulocyte–macrophage colony-stimulating factor; PAMP, pathogen-associated molecular pattern.

Fig. 2. Role of IL-17 in protective immunity versus immunopathology.

During infection, pathogens release pathogen-associated molecular patterns (PAMPs) that bind to pattern recognition receptors (PRRs) and activate innate immune cells, including macrophages and dendritic cells (DCs), which present foreign peptide antigens to T cells and provide a source of T cell-polarizing cytokines. IL-1β and IL-23 activate T helper 17 (T_H17) cells, IL-17-producing CD8⁺ T cells (IL-17⁺CD8⁺), type 3 innate lymphoid cells (ILC3s) and IL-17-secreting γδ T (γδT17) cells, which produce IL-17A and IL-17F as well as other pro-inflammatory cytokines (not shown) that promote the production of neutrophil-recruiting chemokines from epithelial cells (for example, in respiratory tract or intestine). IL-17, together with IFNγ, can also activate macrophages. Activated macrophages and neutrophils phagocytose and kill intracellular bacteria, fungi and protozoan parasites. IL-17A, IL-17F and IL-22 promote the production of antimicrobial peptides (AMPs) and enhance epithelial barrier function. In autoimmune diseases (or infection-indued immunopathology), the same responses, triggered by infection or damage during sterile inflammation (damage-associated molecular patterns; DAMPs), can promote auto-antigen-specific T_H17 cells and γδT17 cells that produce IL-17A and IL-17F, which in combination with tumour necrosis factor (TNF), act on epithelial cells (for example, keratinocytes in psoriasis) to produce chemokines that recruit neutrophils and macrophages, promoting inflammation. IL-17 also activates the production of pro-inflammatory cytokines and matrix metalloproteinases (MMPs) that mediate the tissue damage and inflammation that lead to autoimmune diseases. CXCL, CXC-chemokine ligand.

Fig. 3. Regulation of IL-17-producing cells that mediate pathology during infection or in autoimmune diseases.

IL-17A, IL-17F and tumour necrosis factor (TNF) produced by T helper 17 (T_H17) cells, IL-17⁺CD8⁺ T cells or IL-17-secreting γδ T (γδT17) cells, and IFNγ produced by T_H1 cells and natural killer (NK) cells recruit and/or activate neutrophils and macrophages that kill intracellular bacteria, fungi and small parasites. IL-17 and IL-22 also promote barrier function. These inflammatory responses can result in immunopathology and tissue damage unless they are tightly regulated. Regulation is mediated by thymically derived regulatory T (tT_reg) cells, peripherally induced regulatory T (pT_reg) cells, alternatively activated macrophages, T_H2 cells and type 2 innate lymphoid cells (ILC2). These cells suppress effector T cells either through the production of immunosuppressive cytokines IL-10, TGFβ, IL-35, IL-4 and IL-13 or directly through the co-inhibitory molecules CTLA4 and PD1 expressed on tT_reg cells.