IL17A was initially identified in a subtractive hybridization screen of a rodent T cell library as mouse cytotoxic T lymphocyte-associated antigen 8 (mCTLA8) (Rouvier et al., 1993), but is now recognized as a characteristic cytokine of the Th17 cell subset, which has effector functions distinct from those of Th1 and Th2 cells (Korn et al., 2009; Kurebayashi et al., 2013).

The IL17A gene spans a region of 4252 bp, consisting of three exons.

The transcript is 1859 bp and has a 45 bp 5 UTR, a 468 bp coding sequence, and a 1346 bp 3 UTR.

No pseudogenes homologous to this gene exist elsewhere in the genome.

The IL17A protein is a glycoprotein that can form either a disulfide-linked homodimer or a heterodimer with the IL17F protein. Members of the IL17 protein family (IL17A-F) contain four highly conserved cysteine residues on each monomer (Kolls and Lindén, 2004; Iwakura et al., 2011). Structural analysis of the IL17F protein has revealed that these four cysteines participate in the characteristic cystine-knot formation observed in other growth factors such as nerve growth factor (NGF), transforming growth factor β2 (TGFβ2) and platelet-derived growth factor (PDGF)-BB (McDonald and Hendrickson, 1993), although one of the canonical disulfides of the cystine-knot is absent from the IL17 protein family (Hymowitz et al., 2001). Two additional cysteine residues participate in homodimer formation via inter-chain disulfide bonds. Crystal structures are now available for IL17A in complex with an antibody (Gerhardt et al., 2009), an IL17F/IL17 receptor A complex (Ely et al., 2009) and an IL17A/IL17 receptor A complex (Liu et al., 2013).

The IL17A monomer is a peptide consisting of 155 amino acids. The IL17A peptide comprises a 23 amino acid signal peptide and a 132 amino acid mature peptide. The IL17A homodimer has a molecular weight of 35 kD (Kolls and Lindén, 2004).

IL17A is secreted not only by CD4⁺ T cells (Th17 cells), which also produce IL17F, IL21, and IL22 (Korn et al., 2009; Kurebayashi et al., 2013), but also by CD8⁺ T cells (Tc17 cells), γδ T cells, invariant natural killer T cells (iNKT cells), innate lymphoid cells (ILCs) including lymphoid tissue inducer cells (LTi cells), B cells, neutrophils, and other non-hematopoietic cells (Cua and Tato, 2010). These lymphocytes all express the retinoic acid receptor-related orphan nuclear receptor C (RORC, the human analogue of mouse RORγt, a splice variant of the Rorc gene). RORγt is essential for IL17A production and the development of IL17A-producing cells, at least in lymphocytes, and is thus considered a master regulator of IL17A-producing cells.

Th17 cells
Th17 cells are a subset of helper T cells that have effector functions distinct from those of Th1 and Th2 cells. Early reports showed that stimulation with transforming growth factor β1 (TGFβ1) and IL6 is required to induce differentiation of IL17-producing CD4⁺ T cells (Th17 cells) from naïve CD4⁺ T cells (Korn et al., 2009). More recent reports have shown that Th17 cells can be categorized into two distinct subsets: conventional Th17 cells (Th17(β) cells, also called non-pathogenic Th17 cells), which differentiate in the presence of IL6 and TGFβ1, and Th17(23) cells (also called pathogenic Th17 cells), which differentiate in the presence of IL6, IL23 and IL1β without exogenous TGFβ1 (Ghoreschi et al., 2010; Basu et al., 2013; Kurebayashi et al., 2013). IL6 and IL1β can induce the expression of IL23 receptor in naïve CD4⁺ T cells in the absence of TGFβ1. Th17(β) cells express IL9, IL10, CCL20, and CXCR6 as well as IL17A and IL17F, whereas Th17(23) cells express IL22, CCL9 and CXCR3; relative to Th17(β) cells, Th17(23) cells make a greater contribution to pathogenesis in autoimmune diseases (Ghoreschi et al., 2010). Th17 cells stimulated with IL23, which is secreted by dendritic cells and macrophages following stimulation with Toll-like receptor (TLR) ligands, induce expression of TGFβ3, leading to the induction of pathogenic Th17(23) cells (Lee et al., 2012). These pathogenic Th17 cells are characterized by the expression of T-bet (TBX21, T-box protein 21), a master regulator of Th1-cell development, as well as RORγt. Compared with Th1 and Th2 differentiation, Th17-cell differentiation exhibits plastic or flexible features (Oestreich and Weinmann, 2012; Basu et al., 2013). TGFβ1 signaling induces the expression of both Foxp3 and RORγt in antigen-activated naïve CD4⁺ T cells and is involved in the differentiation of both iTreg and Th17 cells. Therefore, additional factors determine iTreg and Th17 polarization. Furthermore, iTreg and Th17 cells can transdifferentiate under specific conditions (Hoechst et al., 2011). The transition from Th17 cells to Th1 cells is also induced by IL23 and IL12 in a STAT4- and T-bet-dependent manner (Lee et al., 2009; Mukasa et al., 2010).
In addition to RORγt and the aforementioned cytokines, several transcriptional regulators positively regulate Th17 cell differentiation: signal transducer and activator of transcription 3 (STAT3), BATF (basic leucine zipper transcriptional factor, ATF-like), interferon regulatory factor 4 (IRF4), Runt-related transcriptional factor 1 (RUNX1), RORα and aryl hydrocarbon receptor (AHR, a nuclear receptor for a number of low-molecular weight chemicals such as the tryptophan photoproduct 6-formylindolo[3,2-b]carbazole (FICZ)) (Hirahara et al., 2010; Kurebayashi et al., 2013). Moreover, prostaglandin E2, ATP, and C-type lectin ligands act on antigen-presenting cells to facilitate Th17-cell differentiation. By contrast, IL4, interferon-γ (IFNγ), IL27, suppressor of cytokine signaling 3 (SOCS3), and STAT5 all suppress Th17-cell differentiation.

Tc17 cells
CD8⁺ T cells develop into Tc17 cells in the presence of TGFβ1 and either IL6 or IL21, similar to the requirements for Th17-cell development (Intlekofer et al., 2008). Tc17 cells are also characterized by the expression of RORγt, STAT3, RORα and IL23R. However, Tc17 cells do not express Granzyme B, and they exhibit impaired cytotoxic activity relative to conventional cytotoxic CD8⁺ T cells (Huber et al., 2009). A recent report suggested that TGFβ signaling is not required for in vivo differentiation of Tc17 cells (Dwivedi et al., 2012).

γδ T cells
Two distinct subsets of CD27⁺ or CD27^- γδ T cells develop in the mouse fetal thymus: co-stimulation of TCR and CD27 induces CD27⁺ γδ T cells to express T-bet and produce IFNγ whereas the absence of TCR signaling (or weak signaling) promotes the development of IL17A-producing CD27^- γδ T cells, a process controlled by RORγt and RUNX1 (Cua and Tato, 2010; Prinz et al., 2013). Because peripheral CD27^- γδ T cells have permissive histone modification at loci involved in expression of not only Il17a but also Ifng, they can produce both IL17A and IFNγ upon stimulation with IL1β and IL23 (Schmolka et al., 2013). All innate IL17-producing lymphocytes, including γδ T cells, iNKT cells and LTi cells, express RORγt and develop in an IL6-independent manner (Cua and Tato, 2010).

iNKT cells
iNKT cells are activated in response to glycolipid antigens presented by CD1d (Cua and Tato, 2010; Guo et al., 2012). IL17A-producing iNKT cells develop in the thymus, and express RORγt and IL23R. A recent report suggested that iNKT cells can be induced to produce IL17A in the presence of TGFβ1 and IL1β (Monteiro et al., 2013).

LTi cells
Innate lymphoid cells (ILCs), a family of RAG1/2-negative lymphoid cells, require the common cytokine receptor γ-chain (also known as IL2RG) and inhibitor of DNA binding 2 (ID2), a transcriptional repressor (Guo et al., 2012; Fuchs and Colonna, 2013; Spits et al., 2013). LTi cells, which like NK cells are prototypical ILCs, belong to the Group 3 ILCs (ILC3s), defined by the production of IL17A and/or IL22 (Spits et al., 2013). ILC3s require the expression of RORγt for their development, express IL23R and IL1R, and produce IL17A and/or IL22 upon stimulation with IL23 or IL1β.

B cells
A recent report shows that Trypanosoma crusi promotes IL17A production by B cells in human and mouse (Bermejo et al., 2013). T. crusi trans-sialidase mediates addition of sialyl residues onto CD45 expressed on B cells, resulting in induction of IL17A and F via BTK activation without the involvement of the transcriptional factors RORγt and AHR.

Other cells
Although the details of the underlying signaling pathways and transcriptional factors are not known, cells other than lymphocytes, such as Paneth cells in the gut and CD11b⁺Gr1⁺ cells in the injured kidney also produce IL17A (Cua and Tato, 2010).

IL17A is a secreted protein.

IL17A is a pro-inflammatory cytokine that acts on a variety of cells (e.g., fibroblasts, epithelial cells, endothelial cells, and monocytes) to induce the production of other cytokines, including IL6, tumor necrosis factor-α (TNFα), granulocyte-macrophage colony-stimulating-factor (GMCSF), granulocyte colony-stimulating-factor (GCSF), chemokines (chemokine (C-X-C motif) ligand 1 (CXCL1), CXCL2, CXCL5, and CXCL8), antimicrobial peptides (defensins) and matrix metalloproteinases (MMP1, MMP3, and MMP13) (Eyerich et al., 2010; Iwakura et al., 2011). These factors mediate the recruitment, activation and migration of neutrophils and myeloid cells, and also induce angiogenesis and tissue destruction.
IL17A, IL17F, and the IL17A-IL17F heterodimer bind to a heteromeric receptor complex composed of IL17 receptor A (IL17RA) and IL17 receptor C (IL17RC). IL17RA is expressed at high levels in hematopoietic cells and at low levels in epithelial cells, fibroblasts, and endothelial cells (Gaffen, 2009; Iwakura et al., 2011). On the other hand, IL17RC is expressed at low levels in hematopoietic cells and at high levels in the adrenal gland, prostate, liver, and thyroid. IL17RA has higher affinity for IL17A than IL17F, whereas IL17RC has higher affinity for IL17F than IL17A. Although cytokines secreted by most activated helper T cells generally stimulate the Janus kinase (JAK)/STAT pathway, the IL17-family cytokines stimulate signaling pathways involved in the innate immune system, such as the TLR signaling pathway (Gaffen, 2009; Iwakura et al., 2011).
IL17 receptors contain a conserved domain, similar expression to fibroblast growth factor/IL17R (SEFIR), in the cytoplasmic region. This domain is similar to the Toll-/IL1R (TIR) domain (Gaffen, 2009; Iwakura et al., 2011). When the IL17 receptor is activated, the adaptor molecule actin-related gene 1 (ACT1, a U-box E3 ubiquitin ligase) is recruited to the SEFIR domain and mediates the lysine 63-linked ubiquitination of tumor necrosis factor receptor-associated factor 6 (TRAF6) (Gaffen, 2009; Iwakura et al., 2011). Ubiquitinated TRAF6 then activates the transcriptional factor nuclear factor κB (NFκB), various mitogen-activated protein (MAP) kinases including ERKs and p38, and CCAAT/enhancer-binding proteins (C/EBPβ and C/EBPδ).
IL-17A expression and Th17 cell development are remarkably affected not only by microorganisms and tumors, but also by several environmental factors such as nutrients, metabolites, hypoxia, toxins, NaCl concentrations, and circadian rhythm.
The tryptophan photoproduct FICZ positively regulates Th17-cell differentiation through AHR, whereas 2,3,7,8-tetrachlorodibezo-p-dioxin (TCDD) negatively regulates differentiation through that receptor (Quintana et al., 2008; Veldhoen et al., 2008). Activation of mTORC1 (mTOR complex containing mLST8 and Raptor) promotes Th17-cell differentiation via positive regulation of hypoxia-inducible factor 1α (HIF1α expression and the activation of S6 kinase (Barbi et al., 2013; Kurebayashi et al., 2013). HIF1α directly upregulates expression of RORγt and IL17A. Therefore, amino acid deprivation selectively blocks Th17-cell development through inhibition of mTORC1, whereas hypoxia promotes Th17 development through the activation of HIF1α. High levels of lactic acid, secreted from tumors due to the Warburg effect, induce macrophages or monocytes to mediate increased IL17A production by Th17 cells in an antigen-dependent manner, but do not Th17-cell differentiation or proliferation (Shime et al., 2008; Yabu et al., 2011).
The circadian rhythm is controlled by a series of feedback loops between the transcriptional factors, a CLOCK-BMAL1 complex and REV-ERBα (Arjona et al., 2012). The expression of RORγt is suppressed by the leucine zipper transcriptional factor NFIL3, which is negatively regulated by REV-ERBα (Yu et al., 2013). Accordingly, CD4⁺ T cells purified during the day express RORγt at higher levels than those purified at night, and tend to differentiate into Th17 cells.
High salt concentration (e.g., 40 mM NaCl) induces phosphorylation of p38 and the expression of serum glucocorticoid kinase 1 (SGK1) and nuclear factor of activated T-cells 5 (NFAT5) to promote the IL23-dependent differentiation of pathogenic Th17 cells (Kleinewietfeld et al., 2013; Wu et al., 2013a). In vivo, a high salt diet promotes Th17-cell differentiation and exacerbates neuropathy in mice with experimental autoimmune encephalomyelitis.

IL17A is a prototypical member of the IL17 family. This family includes six proteins: IL17A, IL17B, IL17C, IL17D, IL17E (also called IL25), and IL17F. Interleukins 17A-F are not homologous to any other known proteins. IL17A has the highest sequence identity with IL17F (46.5 %). It is less similar to the other IL17 family members: IL17B, 26.4 %; IL17C, 28.9 %; IL17D, 21.8 %; and IL17E, 17.7 %.