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THE IL-17/T_H17 PATHWAY: A PRIMER

IL-17 (IL-17A) was discovered in 1993 but was largely overlooked until 2005 with the revamping of the T_H1/T_H2 paradigm to include the T_H17 subset of CD4⁺ T cells (48). IL-17–expressing populations include the conventional adaptive T_H17 subset of T cells as well as innate-acting lymphocyte populations, including γδ T cells, natural killer (NK) T cells, “innate lymphoid cells” (ILCs), T cell receptor αβ⁺ (TCRαβ⁺) “natural” T_H17 cells (nT_H17), and Foxp3⁺ T regulatory cell (T_reg)–like cells, collectively termed “type 17” (49). Some evidence for IL-17 expression in B cells and myeloid cells is also reported, though this is controversial. Although requirements for inducing IL-17 in type 17 cell types vary, IL-23 and/or IL-1 are usually implicated, in conjunction with signals from pathogen-derived PAMPs (pathogen-associated molecular patterns) or the inflammatory environment. Type 17 cells also produce other cytokines, such as IL-17F, IL-22, and GM-CSF (granulocyte-macrophage colony-stimulating factor). The IL17F gene is closely linked to IL17A; these cytokines form not only homodimers but also heterodimers and signal through the same receptor, with varying affinities (IL-17A > IL-17A/F > IL-17F). The transcription factor RORγt (retinoic acid–related orphan receptor γt) is viewed as a “master regulator” of T_H17 cells and, in combination with STAT3 (signal transducer and activator of transcription 3) and other transcription factors, is required for IL-17A and IL-17F expression. Type 17 cells express the IL-23 receptor (IL-23R), but IL-23 per se is not essential for IL-17 expression (50). Type 17 cells are also characterized by expression of CCR6, which binds the mucosal chemokine CCL20 (51). Consequently, type 17 cells are highly enriched at mucosal surfaces and play key roles in barrier immunity. This is especially evident for oral immune responses, as outlined below.

Although produced almost exclusively by lymphocytes, IL-17 signals in the nonhematopoietic compartment, thus bridging the immune system and inflamed tissues, especially mucosae. The IL-17 signaling pathway has recently been described in extensive detail (52). Briefly, IL-17 engages a heterodimeric receptor (IL-17RA and IL-17RC) found mainly in mesenchymal and epithelial cell types. All known downstream IL-17 signaling events are initiated by the multifunctional adaptor Act1, which is recruited to the IL-17R after ligand engagement. Act1 recruits diverse TRAF proteins, which regulate inflammatory mRNA expression through transcriptional and posttranscriptional pathways. Best described is TRAF6-dependent activation of the NF-κB (nuclear factor κB)/inhibitor of κBξ (IκBξ), C/EBP (CCAAT/enhancer binding protein), and AP-1 (activator protein–1) transcription factors, which orchestrate new gene transcription. Often less appreciated, IL-17 is also a potent regulator of mRNA fate (stabilization, degradation, and translation), a pathway initiated by TRAF2/5 and orchestrated by a suite of RNA binding proteins including Act1 itself. The ability of IL-17 to stabilize mRNA posttranscriptionally explains how this cytokine is able to synergize promiscuously with diverse inflammatory signals. That is, regardless of how target mRNAs are up-regulated by specific transcription factors, IL-17–mediated signals that stabilize or destabilize the resulting mRNA determine the magnitude of downstream target gene expression. The circuitry involved can be quite complex, and interestingly, several of the relevant RNA binding proteins were first identified in studies of IL-17–dependent oral candidiasis (52).

IL-17 function has been inferred quite accurately from its target genes. Transcriptomic studies have revealed a consistent core IL-17 “gene signature,” which includes neutrophil-activating genes (CXC chemokines and G-CSF), antimicrobial proteins [β-defensins (BDs), S100A8/9, and lipocalin-2], cytokines (IL-6 and GM-CSF), and transcription factors (IκBξ, C/EBPβ, and C/EBPδ) (52). IL-17 also induces many tissue- or cell type–specific genes. Consistently, IL-17 is a potent inducer of barrier host defense against microbes that are sensitive to neutrophils and antimicrobial protein activity, including periodontal pathogens and C. albicans, among others. Although a potent inducer of potentially damaging inflammation, IL-17 also drives tissue repair, a property evident in some of the genes that it regulates (53). In the gut, barrier tissue repair appears to be a dominant response, perhaps explaining why anti–IL-17 therapy in humans failed in IBD (inflammatory bowel disease) trials (54). In the oral mucosa, far less is known about the extent to which IL-17 drives tissue repair. Although most of the documented IL-17 signaling events occur at barrier surfaces, recent data indicate roles in controlling metabolism in stromal lymph node tissue as well. Roles in cancer have also been described (52).