Mucocutaneous IL-17 immunity in mice and humans: host defense vs. excessive inflammation

Abstract

Interleukin (IL)-17A is a pro-inflammatory cytokine in mice and humans. It is recognized as a key factor for the protection of mice against various pathogens, but it also underlies pathogenic inflammatory responses in numerous mouse models. The inborn errors of IL-17A- and IL-17F-mediated immunity identified in humans in the last decade have revealed that IL-17A and IL-17F are key players in mucocutaneous immunity to Candida albicans, and, to a lesser extent, Staphylococcus aureus. By contrast, there is currently no genetic evidence for a causal link between excess of IL-17 and autoimmunity, autoinflammation, or allergy in humans. We discuss here the physiological and pathological roles of mouse and human IL-17A and IL-17F in host defense and excessive inflammation. We highlight recent advances in our understanding of the consequences deficient or excessive IL-17 immunity at various mucocutaneous sites, including the oral cavity, skin, intestine, lungs, and vagina.

IL-17 cytokines and receptors

The IL-17 cytokine family has six members in mice and humans: IL-17A (also known as IL-17), IL-17B, IL-17C, IL-17D, IL-17E (also known as IL-25), and IL-17F (Figure 1). The founding member, IL-17A, was originally called cytotoxic T-lymphocyte-associated antigen 8 (CTLA-8) when it was first cloned in 1993¹. It was subsequently renamed IL-17², and, more recently, IL-17A³. The IL-17F protein is the protein of this family most closely related to IL-17A, and the genes encoding these two cytokines are located on the same chromosome, in both mice and humans⁴. T_H17 cells, a distinct lineage of CD4⁺ T helper cells discovered in mice in 2005, have been identified as the principal source of IL-17A and IL-17F^5–7 (Figure 2). IL-22 and IL-26 (absent in mice) are the other effector cytokines preferentially produced by T_H17 cells^{8, 9}. CD8⁺ T cells have also been reported to produce IL-17A and IL-17F, and are known as Tc17 cells^{10, 11} (Figure 2). The other cells capable of producing IL-17A and IL-17F include γδ T cells^{12, 13}, invariant natural killer T (iNKT) cells^{14, 15}, natural killer (NK) cells^{16, 17}, and type 3 innate lymphoid cells (ILC3s)^18–21 (Figure 2). It remains unclear whether neutrophils produce IL-17A^22–25. IL-17A and IL-17F have a similar pattern of expression in cells, driven by signal transducer and activator of transcription 3 (STAT3), RAR-related orphan receptor γT (RORγT), and RORα^26–28. They also display a similar cysteine knot configuration⁴, acting both as IL-17A/IL-17A and IL-17F/IL-17F homodimers and as IL-17A/IL-17F heterodimers^29–31. IL-17A homodimers have been shown to be more potent than IL-17F homodimers in fibroblasts, macrophages, and epithelial cells, in terms of their ability to induce pro-inflammatory cytokines and chemokines, such as IL-6 and growth-related oncogene-α (GRO-α); IL-17A/IL-17F heterodimers have intermediate activity^29–31.

Figure 1. The IL-17 cytokine and receptor family.

The IL-17 cytokine family has six members (IL-17A, IL-17B, IL-17C, IL-17D, IL-17E, and IL-17F), whereas the IL-17 receptor family has five members (IL-17RA, IL-17RB, IL-17RC, IL-17RD, and IL-17RE). IL-17RA forms heterodimeric complexes with other subunits to induce signaling by IL-17 cytokines. The IL-17RA/IL-17RC complex binds to IL-17A/IL-17A and IL-17F/IL-17F homodimers and IL-17A/IL-17F heterodimers. The IL-17RA/IL-17RB and IL-17RA/IL-17RE receptors recognize IL-17E and IL-17C, respectively. The ligand for the IL-17RA/IL-17RD receptor complex and the receptors for IL-17B have not yet been identified. ACT1 serves as a key adaptor molecule, which is recruited to the known IL-17 receptors.

Figure 2. IL-17A- and IL-17F-mediated immunity.

T_H17, Tc17, γδ T, ILC3s, iNKT, and NK cells are the major IL-17A- and IL-17F-producing cells, whereas macrophages, fibroblasts, keratinocytes, endothelial and epithelial cells are the main IL-17RA/IL-17RC-expressing cells. The target genes of IL-17A and IL-17F include pro-inflammatory cytokines, chemokines, antimicrobial peptides, and matrix metalloproteinases (MMPs). ICAM-1, intercellular adhesion molecule 1; VCAM-1, vascular cell adhesion molecule 1; COX-2, cyclooxygenase 2; VEGF, vascular endothelial growth factor; PGE2, prostaglandin E2; iNOS, inducible nitric oxide synthase; NO, nitric oxide.

Soon after the discovery of IL-17A, IL-17RA (also known as IL-17R) was identified as the founding member of the IL-17 receptor family in mice and humans². This family has five members: IL-17RA, IL-17RB, IL-17RC, IL-17RD, and IL-17RE (Figure 1). The subunits of the IL-17 receptor, containing a conserved SEFIR (similar expression of fibroblast growth factor and IL-17R) domain, form various heterodimeric complexes with IL-17RA to induce signaling by IL-17A and IL-17F (IL-17RA/IL-17RC), IL-25 (IL-17RA/IL-17RB), and IL-17C (IL-17RA/IL-17RE)³² (Figure 1). In each case, functional mouse and human IL-17 receptors bind SEFIR domain-containing adaptor nuclear factor-κB (NF-κB) activator 1 (ACT1) to mediate the downstream NF-κB, mitogen-activated protein kinase (MAPK), and CCAAT/enhancer-binding protein (C/EBP) signaling pathways³². The receptors for IL-17B and the ligand for the IL-17RA/IL-17RD receptor complex have not yet been identified³² (Figure 1). IL-17RA and IL-17RC are the best-characterized members of the IL-17 receptor family, largely because of their interaction with IL-17A and IL-17F. IL-17RA is ubiquitously expressed, whereas IL-17RC expression is mostly restricted to non-hematopoietic cells³³. In humans, the affinity of IL-17RA binding is much higher for IL-17A than for IL-17F³⁴. By contrast, IL-17RC and IL-17RA/IL-17RC bind IL-17A and IL-17F with similar affinities³⁴. In mice, IL-17RA binds both IL-17A and IL-17F, but IL-17RC binds strongly only to IL-17F³⁴. The affinity of IL-17RA/IL-17RC binding for IL-17A and IL-17F has not been tested³⁴. IL-17A and IL-17F therefore mostly activate non-hematopoietic cells (Figure 2). Genes encoding pro-inflammatory cytokines and chemokines are the major targets of IL-17A and IL-17F³³ (Figure 2). For example, IL-6, granulocyte colony-stimulating factor (G-CSF), and granulocyte-macrophage colony-stimulating factor (GM-CSF) regulate myeloid cell functions and inflammatory responses, whereas GRO-α, CXC chemokine 2 (CXCL2), and CXCL5 act as chemoattractants for monocytes and neutrophils³³. Antimicrobial peptides, including β-defensins in particular, are also induced by IL-17A and IL-17F at the epithelial barrier, to protect the host against a wide range of microorganisms³³ (Figure 2). CC chemokine 20 (CCL20) recruits IL-17A- and IL-17F-producing cells expressing CC chemokine receptor 6 (CCR6)³³ (Figure 2).

IL-17 in the oral cavity and skin

In mice, IL-17A, IL-17F, and their receptors, IL-17RA/IL-17RC, have been shown to play a major role in host defense against experimental infections of the oral cavity and skin caused by C. albicans and S. aureus. In a mouse model of oropharyngeal candidiasis (OPC), IL-17RA- and IL-17RC-deficient mice, like anti-IL-17A/IL-17F antibody (Ab)-treated mice, were found to have higher fungal burdens on the tongue than wild-type controls^35–37. Neutrophil recruitment and function, which have been reported to be important for host defense against OPC in mice³⁸, were essentially normal in these mice³⁷. A recent study, using mice with a conditional deficiency of IL-17RA in superficial oral and esophageal epithelial cells, suggested that the IL-17RA-dependent antifungal response was mediated by the production of β-defensin 3³⁹. Moreover, ILCs, γδ T and thymus-derived T_H17 cells (natural T_H17 cells) have been shown to be major sources of IL-17A and IL-17F in response to C. albicans in mice, and indispensable for IL-17-mediated antifungal immunity in the oral mucosa^40–42. IL-17A-deficient mice are more susceptible to cutaneous infection with C. albicans than wild-type mice⁴³. Mice lacking IL-12p40 or IL-23p19, the two subunits of IL-23, which is essential for T_H17 cell development and maintenance in mice⁴⁴, also have high fungal burdens in the skin when challenged with C. albicans⁴³. These results suggest that the immunity mediated by IL-17A and IL-17F is the key to mucocutaneous protection against C. albicans in mice, at least in experimental conditions. However, C. albicans is a commensal in humans, but not in mice. In addition, IL-17RA- and γδ T cell-deficient mice have larger skin lesions with higher bacterial counts upon cutaneous S. aureus infection, and these phenotypes can be rescued by the administration of recombinant IL-17A in γδ T cell-deficient mice⁴⁵. Furthermore, mice lacking both IL-17A and IL-17F are particularly susceptible to S. aureus infection, developing mucocutaneous abscesses around the nose and mouth⁴⁶. These findings highlight the crucial importance of IL-17A and IL-17F in protective immunity to experimental infection with S. aureus, which is commensal in mice⁴⁷.

Humans with inborn errors of IL-17 immunity present chronic mucocutaneous candidiasis (CMC)^{48, 49}. CMC is characterized by recurrent or persistent lesions of the skin, nails, oral, and genital mucosae caused by Candida spp., mostly C. albicans^50–52. Autosomal recessive (AR) IL-17RA and autosomal dominant (AD) IL-17F deficiencies were the first genetic etiologies identified in patients with ‘isolated’ inherited CMC, who develop CMC with no other prominent clinical signs except staphylococcal skin lesions and pulmonary bacterial diseases in some cases⁵³. AR IL-17RA deficiency has been reported in 23 patients from 13 unrelated kindreds, and shown to be caused by 12 different homozygous IL17RA mutations and one large homozygous deletion encompassing IL-17RA and adenosine deaminase 2 (ADA2)^53–55. These patients lack fibroblast responses to IL-17A and IL-17F homodimers and heterodimers and leukocyte responses to IL-25^{53, 55}. These cellular responses are also impaired in patients with AR ACT1 deficiency (2 patients from 1 kindred)⁵⁶. By contrast, patients with AD IL-17F (5 patients from 1 kindred) or AR IL-17RC (3 patients from unrelated kindreds) deficiencies display impaired or abolished responses to IL-17A and IL-17F homodimers and heterodimers in fibroblasts, but their leukocytes respond normally to IL-25^{53, 57}. Interestingly, staphylococcal diseases are frequently seen in patients with AR IL-17RA or ACT1 deficiencies, but not in those with AD IL-17F or AR IL-17RC deficiencies^{48, 49}. It has thus been suggested that compromised responses to IL-25 or another IL-17RA-dependent cytokine may account for staphylococcal diseases in patients with inborn errors of IL-17 immunity. Taken together, these data reveal that human IL-17 immunity is indispensable for mucocutaneous immunity to C. albicans and S. aureus in natural conditions, especially in the oral cavity and skin.

Psoriasis is an autoimmune and inflammatory skin disorder characterized by red scaly patches of hyperproliferating keratinocytes and hyperkeratinosis^58–61. Following the intradermal injection of IL-23, wild-type mice develop erythema, epidermal hyperplasia, and massive neutrophil infiltration⁶². By contrast, IL-17RA- or IL-17A- (or even IL-22-)deficient mice are resistant to IL-23-induced psoriasis-like epidermal hyperplasia and inflammation^{63, 64}. Dermal γδ T cells, which constitutively express the IL-23 receptor (IL-23R), have been shown to be the principal producers of IL-17A in mouse skin following stimulation with IL-23⁶³. Ablation of the IL-17RA or ACT1 gene also protects mice from imiquimod-induced psoriasis-like skin inflammation^65–67. Furthermore, K5.Stat3C transgenic mice, which express STAT3 constitutively in keratinocytes, develop psoriasiform lesions following treatment with 12-O-tetradecanoylphorbol-13-acetate (TPA), whereas the Ab-mediated neutralization of IL-12p40, IL-23p19, or IL-17A, or deletion of the IL-17A gene attenuates the development of psoriasis-like lesions⁶⁸. These data suggest that the IL-23-T_H17-IL-17A axis contributes to the pathogenesis of skin lesions in mouse models of psoriasis. Consistent with this hypothesis, several T_H17-associated molecules, including IL-17A, IL-17F, IL-22, IL-26, and RORγT, are strongly expressed in the psoriatic skin lesions of patients, probably due to the production of IL-23 by dendritic cells (DCs) in the skin^{9, 69}. Genome-wide association studies (GWAS) in humans have also identified polymorphisms weakly associated with psoriasis close to the IL23R and ACT1 genes^{70, 71}. Genetic proof of the involvement of IL-17 in the pathogenesis of human psoriasis is, however, lacking, in the absence of known gain-of-function (GOF) mutations. The known monogenic forms of psoriasis include AR deficiency of IL-36-receptor antagonist (DITRA) and AD caspase recruitment domain-containing protein 14 (CARD14) GOF^72–76. Nevertheless, IL-23 and IL-17A have been identified as potential treatment targets in psoriasis. Human monoclonal Abs targeting IL-23p19 (risankizumab, guselkumab, and tildrakizumab) are currently in phase III trials, and have yielded encouraging early efficacy and safety results^77–79. Anti-IL-17A (secukinumab and ixekizumab) and anti-IL-17RA (brodalumab) Abs have recently been approved by the US Food and Drug Administration (FDA) for psoriasis treatment, and have been shown to clear up skin lesions totally after 12 weeks of treatment in more than a quarter of the participants in the phase III trial^80–82.

IL-17 in the intestine

Not only is the immunity mediated by IL-17A and IL-17F crucial for protection against C. albicans and S. aureus, it also protects mice against experimental infection of the intestine with Citrobacter rodentium. IL-12p40-, IL-23p19-, IL-17A-, IL-17F-, IL-17A/IL-17F double-, and IL-22-deficient mice are more susceptible to C. rodentium infection than wild-type mice^{46, 83, 84}. Mortality is higher in IL-12p40-, IL-23p19-, or IL-22-deficient mice challenged with C. rodentium than in wild-type mice challenged with the same bacterium^{83, 84}. IL-22 is induced by IL-23 in the colon and maintains colonic epithelial integrity during the early phase of C. rodentium infection in mice, by inducing the regenerating islet-derived (Reg) family of antimicrobial proteins⁸⁴. Likewise, in response to C. rodentium infection, IL-17A-, IL-17F-, and IL-17A/IL-17F double-deficient mice have higher bacterial burdens and display more severe colonic inflammation, probably due to the impairment of β-defensin production⁴⁶. The specific disruption of IL-17RA in mouse intestinal epithelial cells is associated with segmented filamentous bacteria (SFB) overgrowth and lower mRNA levels of α-defensins, NADPH oxidase 1 (Nox1), and polymeric immunoglobulin receptor (pIgR), as well as poor fecal secretory IgA production⁸⁵. However, it remains unclear whether IL-17A and IL-17F protect against experimental infection of the intestine with Salmonella enterica serovar Typhimurium. In a mouse model of streptomycin-pretreated S. typhimurium infection, IL-17RA-deficient mice challenged with strain ATCC 14028 display higher levels of bacterial translocation from the intestine to the mesenteric lymph nodes and spleen⁸⁶. By contrast, IL-17A-, IL-17F-, or IL-17RA-deficient mice, and mice treated with anti-IL-17A plus IL-17F Abs, display levels of bacterial dissemination and cecal inflammation similar to those of wild-type mice following challenge with strain SL1344⁸⁷. Local neutralization of IL-17A in the intestinal lumen decreases bacterial clearance and exacerbates epithelial damage in mice infected with S. typhimurium strain LT2⁸⁸. Further studies are, therefore, required, to clarify the contribution of IL-17 immunity to intestinal protection against experimental S. typhimurium infection in mice. In humans, deficiencies of IL-17 immunity do not seem to cause a predisposition to pathogenic infections in the intestine, at least among the patients identified to date^{48, 49}.

Inflammatory bowel disease (IBD), including ulcerative colitis (UC) and Crohn’s disease (CD), is a group of autoinflammatory disorders characterized by inflammation of the colon and small intestine⁵⁸. The precise role of IL-17A- and IL-17F-mediated immunity in experimental inflammatory colitis in mice remains a matter of debate. In a mouse model of acute trinitrobenzenesulfonic acid (TNBS)-induced colitis, IL-17RA-deficient mice are protected from weight loss and colonic inflammation, and the administration of an IL-17RA IgG1 fusion protein improves established colonic inflammation in wild-type mice⁸⁹. Mice lacking IL-17A or IL-17F are also resistant to dextran sodium sulfate (DSS)-induced colitis, displaying milder acute intestinal inflammation^{90, 91}. However, some studies have suggested that the neutralization or genetic ablation of IL-17A, and the epithelial-specific deletion of ACT1 result in severe DSS-induced colitis in mice^91–94. These conflicting findings may result from differences in experimental setting, including the genetic background and intestinal microbiota of the mice. Moreover, in a mouse model of T cell-mediated colitis, the adoptive transfer of IL-17A- or IL-17RA-deficient T cells in recombination activating gene 1 (Rag1)-deficient mice, which lack mature T and B cells, led to exacerbated colitis⁹⁵. Multidrug resistance 1a (Abcb1a)-deficient mice infected with Helicobacter bilis develop spontaneous colitis, and the neutralization of IL-17A or IL-17RA accelerates death, by greatly weakening the intestinal epithelial barrier and increasing colonic inflammation⁹⁶. It has been suggested that the principal function of IL-17A and IL-17RA in experimental colitis is the maintenance of intestinal barrier integrity rather than driving pathogenic inflammation. Clinical trials of anti-IL-17A (secukinumab) and anti-IL-17RA (brodalumab) Abs in patients with moderate-to-severe CD have reported no improvement, or even a worsening of disease, on treatment^{97, 98}. The high levels of mRNA for T_H17 signature cytokines, including IL-17A, IL-17F, IL-22, and IL-26, in the intestinal mucosa of patients with IBD may therefore be beneficial^99–102.

IL-17 in the lungs

The protective role of IL-17 cytokines and receptors in host defense against microorganisms was first described in a mouse model of Klebsiella pneumoniae infection. IL-17RA-deficient mice display high mortality rates, delayed neutrophil recruitment, and poor G-CSF and CXCL2 expression in the lungs¹⁰³. This observation was supported by the findings of a recent study of mice with a conditional deficiency of IL-17RA or IL-17RC in the lung epithelium. These mice display compromised K. pneumoniae clearance, with impaired neutrophil recruitment in response to IL-17A and low levels of CXCL5 production¹⁰⁴. Similarly, mice lacking IL-17A due to a genetic deficiency or Ab-mediated neutralization are more susceptible to K. pneumoniae infection than wild-type mice^105–107. It has been shown that IL-17A- and IL-17F-producing γδ T cells are essential to protect mice against K. pneumoniae¹⁰⁶, whereas ILC3s also play a crucial role in activating inflammatory monocytes during infection¹⁰⁷. In a mouse model of S. aureus pneumonia, IL-17A-, IL-17F-, and IL-17RA-deficient mice have been shown to have large bacterial burdens in the lungs¹⁰⁸. In addition, the genetic deletion of IL-17A or IL-17RA leads to higher bacterial counts in the lungs, associated with lower levels of G-CSF production and an impairment of IL-12-dependent interferon-γ (IFN-γ) responses in mice infected with a live vaccine strain (LVS) of Francisella tularensis¹⁰⁹. IL-17A induces the production of IL-12 and IFN-γ in antigen-presenting cells (APCs) and enhances bacterial clearance following infection with F. tularensis LVS¹⁰⁹. Furthermore, upon challenge with Chlamydia muridarum, mice in which IL-17A has been neutralized display compromised Chlamydia-specific T_H1 responses, with greater bacterial growth in the lungs, and lower survival^{110, 111}. In a DC/T-cell coculture system, DCs isolated from mice in which IL-17A was neutralized induced lower levels of IFN-γ production by Chlamydia-specific T cells than those derived from wild-type mice¹¹⁰. Collectively, these findings suggested that the immunity mediated by IL-17A and IL-17F makes a major contribution to the protection of mice against experimental bacterial infections of the lungs. Consistent with this hypothesis, various bacterial infections of the respiratory tract have been seen in patients with AR IL-17RA deficiency⁵⁵.

Asthma is classically considered to be a T_H2-mediated allergic disorder characterized by eosinophilic inflammation and airway hyperresponsiveness (AHR) that ultimately gives rise to obstructive airway and breathing problems⁵⁸. In a mouse model of ovalbumin (OVA)-induced asthma, IL-17RA-deficient mice display impaired eosinophil recruitment and compromised T_H2 responses¹¹². Likewise, IL-17A-deficient mice have lower levels of OVA-induced AHR and pulmonary inflammation¹¹³. The adoptive transfer of OVA-specific T_H17 cells in recipient mice leads to an influx of neutrophils in the airways and AHR, whereas the transfer of OVA-specific T_H2 cells results in the migration of lymphocytes and eosinophils into the lungs and AHR, following OVA challenge¹¹⁴. Treatment with dexamethasone attenuates the airway inflammation and AHR induced by T_H2 cells, but not those induced by T_H17 cells¹¹⁴. These results suggest a potential role for T_H17 cells in steroid-resistant asthma in mice. In a mouse model of allergen-induced asthma, the neutralization of both IL-13 and IL-17A protects mice from eosinophilic and neutrophilic inflammation and AHR¹¹⁵, suggesting that the combined targeting of T_H2 and T_H17 cells may maximize therapeutic efficacy. Moreover, a subset of IL-17A-producing T_H2 (T_H2/T_H17) cells has been shown to induce higher levels of heterogeneous inflammatory leukocyte infiltration and to exacerbate asthma relative to classical T_H2 and T_H17 cells¹¹⁶. Consistently, several studies have shown that IL-17A is upregulated in the sputum and bronchial biopsies of patients with asthma and that the production of this cytokine is correlated with disease severity¹¹⁷. It has also been suggested that a higher frequency of T_H2/T_H17 cells in bronchoalveolar lavage fluid is associated with a more severe form of asthma in humans¹¹⁸. However, a clinical trial showed that anti-IL-17RA Ab (brodalumab) alone had no effect in patients with moderate-to-severe asthma¹¹⁹.

Chronic obstructive pulmonary disease (COPD), encompassing chronic bronchitis and emphysema, is a progressive and largely irreversible disorder resulting in airflow limitation⁵⁸. It is caused by long-term exposure to toxic inhalants, and is most often associated with cigarette smoke⁵⁸. In mice, cigarette smoke promotes T_H17 cell differentiation in vitro and in vivo via the aryl hydrocarbon receptor^{120, 121}. IL-17A- or IL-17RA-deficient mice are resistant to emphysema^{120, 121}, whereas transgenic mice displaying lung-specific IL-17A expression (Cc10-Il17a) develop severe emphysema in response to cigarette smoke¹²¹. The adoptive transfer of lung APCs isolated from mice with emphysema induces emphysema and an increase in inflammation after 12 weeks in the absence of smoke in wild-type, but not in IL-17A-deficient recipient mice¹²¹. In addition, the neutralization of IL-17A attenuates smoke-induced neutrophilic inflammation of the airways in mice¹²². Large numbers of T_H17 cells and the overproduction of IL-17A have also been observed in the lungs of mice treated with porcine pancreatic elastase¹²³. IL-17A-deficient mice display lower levels of elastase-induced pulmonary inflammation and emphysema than wild-type mice¹²³. Furthermore, in two mouse models of airway fibrosis triggered by COPD-relevant stimuli, exposure to an adenoviral IL-1β vector (Ad-IL-1β) or cigarette smoke in combination with viral mimetic poly(I:C), the knockout of IL-17RA or the neutralization of IL-17A or IL-17RA results in lower levels of airway fibrosis and inflammation¹²⁴. Finally, there is growing evidence to suggest that patients with COPD have higher proportions of T_H17 cells among their peripheral blood mononuclear cells (PBMC) and high levels of IL-17A and IL-17F on bronchial biopsies^{125, 126}. High levels of RORγT mRNA have also been reported in the lungs of patients with COPD¹²⁷. However, a phase II trial of anti-IL-17A Ab (CNTO 6785) did not show any significant efficacy in the treatment of patients with symptomatic moderate-to-severe COPD¹²⁸.

IL-17 in the vagina

There is increasing evidence to suggest that IL-17A- and IL-17-mediated immunity may be involved in host defense in the mouse vagina. For instance, mice in which IL-17A or IL-17RA has been neutralized are more susceptible to Neisseria gonorrhoeae infection than wild-type mice¹²⁹. They die more rapidly and have higher bacterial burdens and delayed neutrophil recruitment to the vagina during N. gonorrhoeae infection¹²⁹. By contrast, ablation of the IL-17A gene results in a lower bacterial load in the vagina upon vaginal infection with C. muridarum¹³⁰, whereas the knockout of IL-17RA does not¹³¹. Both types of mutant mouse display lower levels of neutrophil influx into the vagina^{130, 131}, but IL-17A-deficient mice have high levels of Chlamydia-neutralizing Ab in the serum¹³⁰, whereas IL-17RA-deficient mice display higher levels of macrophage influx and tumor necrosis factor-α (TNF-α) production, possibly compensating for the impaired Chlamydia-specific T_H1 response and IFN-γ production¹³¹. However, the role of IL-17 immunity in vaginal C. albicans infection in mice remains unclear. In a mouse model of estrogen-induced vulvovaginal candidiasis (VVC), wild-type mice produce larger amounts of IL-17A and display massive neutrophil influx into the vagina upon C. albicans chanllenge¹³², and treatment with halofuginone, a specific inhibitor of mouse and human T_H17 cell differentiation¹³³, results in a higher fungal load and greater β-defensin 2 production¹³². By contrast, wild-type and IL-23p19-, IL-17RA-, and IL-22-deficient mice have similar vaginal fungal burdens and similar levels of neutrophil infiltration following inoculation with C. albicans¹³⁴. Humans with inborn errors of IL-17 immunity do not seem to be susceptible to pathogenic infections of the vagina^{48, 49}.

Concluding remarks

The discovery of T_H17 cells has greatly expanded and advanced our understanding of the roles of IL-17A, IL-17F, and their receptors in autoimmunity, autoinflammation, allergy, and host defense (Figure 3). However, the role of these molecules in malignancy, the fifth broad category of phenotypes associated with inborn errors of immunity, has not been studied. The development of mucocutaneous carcinomas in patients with CMC and inborn errors of IL-17 immunity suggests that IL-17 may play a role in immunosurveillance, at least indirectly, via host defense against C. albicans. Treatments with IL-17A and IL-17RA inhibitors have been shown to be beneficial in diseases characterized by excessive inflammation, such as psoriasis, but human genetic studies have shown that IL-17A and IL-17F play an essential role in mucocutaneous immunity to C. albicans and, to a lesser extent, S. aureus. A higher percentage of fungal infections, properly managed with antifungal treatments, has been reported in some trials of the blockade of IL-17-mediated immunity (e.g. anti-IL-17A or anti-IL-17RA Abs in patients with psoriasis or psoriatic arthritis)^{135, 136}. Thus, fine control of balance between pathogenic and protective IL-17 immunity will be of crucial importance in the development of future therapeutic strategies for treating inflammatory and infectious diseases.

Figure 3. IL-17A and IL-17F in host defense and excessive inflammation.

In mice, deficient IL-17A- and IL-17F-mediated immunity predisposes to various pathogenic infections of the oral cavity, skin, intestine, lungs, and vagina, whereas excessive IL-17A- and IL-17F-mediated immunity induces pathological inflammation in the skin, intestine, and lungs. Human inborn errors of IL-17 immunity present chronic mucocutaenous candidiasis (CMC) in the oral cavity, CMC and staphylococcal diseases in the skin, and various bacterial infections in the lungs. Treatments with anti-IL-17A and IL-17RA inhibitors are beneficial for patients with psoriasis characterized by excessive inflammation in the skin.