Many cell types including immune and nonimmune cells are able to produce IL-17 cytokines for host defense. In particular, innate immune cells such as γδT cells [1]. Recent studies indicate that γδT cells are the major initial IL-17 producers in acute infections [2]. Some γδT cells have IL-17-producing capacities without explicit induction of an immune response. These γδT cells preferentially reside in the skin and mucosal membranes [2]. Other innate immune cells producing IL-17 include NK, iNKT, mast cells, lymph tissue inducer (LTi) cells, group 3 innate lymphoid cells (ILC3) [3], and macrophages. Adoptive immune cells producing IL-17 include Th17 cells and Tc17 cells. Nonimmune cells include epithelial cells and keratinocytes, which are more likely for host defense. Adoptive immune cells producing IL-17 include Th17 cells and Tc17 cells. While CD8⁺ Tc17 cells are more likely to participate in host defense, CD4⁺ Th17 cells are more likely to participate in chronic inflammation in inflammatory diseases. ILC3 cells are found in the lung, gut, and skin. Currently, IL-17-producing ILC3 cells are often associated with inflammation [3–5], but their physiological property in host defense is not fully appreciated (Table 2.1) [6].

Many cell types express IL-17 receptors indicating the wide range of effects that IL-17 cytokines can take place to influence cell biology. The major physiological function of IL-17 is mediating host mucosal defense against extracellular bacterial and fungal infection. This function is mainly achieved via induction of local tissue inflammation as a result from cooperation of IL-17 with other cytokines and mediators.

The major feature of IL-17 signal-deficient mice is the reduced number of neutrophils at the site of inflammation, which indicates the critical role of IL-17 in recruiting neutrophils. IL-17RA knockout mice which were challenged with Klebsiella pneumoniae displayed a significant reduction of neutrophils in the infected lungs with 100 % mortality [7]. The reduced accumulation of neutrophils in the infection sites is associated with decreased expression of granulocyte colony-stimulating factor (G-CSF) and MIP-2 in the lung [7]. Inversely, ectopic expression of IL-17 resulted in a strong neutrophilic response [8]. However, IL-17 does not affect function of neutrophils. Neutrophils from IL-17RA-deficient mice are intrinsically normal as they migrate normally in response to attractants and produce normal levels of MPO [9]. Subsequent in vitro studies have demonstrated that IL-17A induces expression of CXC chemokines by epithelial cells (Table 2.2) and other cell types. Many CXC chemokines are induced by IL-17A. The key chemokines in mice are CXCL1 and CXCL5 [10], while IL-8 (CXCL8) in humans [11] are the most neutrophil-attracting molecules induced by IL-17A. These data indicate that IL-17A indirectly act on neutrophils.

IL-17A-induced inflammation is also via induction of other pro-inflammatory cytokines. As shown in Table 2.2, several studies demonstrated that IL-17A is a potent inducer of IL-6 production by several cell types. IL-6 is a potent stimulator for Th17 cell differentiation suggesting a positive feedback mechanism induced by IL-17A [12]. Other inflammatory cytokines induced by IL-17A include tumor necrosis factor (TNF), IL-1β, and granulocyte-macrophage colony-stimulating factor (GM-CSF) [25, 26]. IL-17 synergizes with TNF and IL-1β in induction of CXC chemokine expression [13, 14, 19]. IL-17 is also a potent inducer for NO synthase and cyclooxygenase expression and leads to an increase in nitric oxide (NO) and prostaglandin E2 (PGE2) production in various cell types, and this process is synergized by TNF and IL-1β [37, 38].

In addition, IL-17A contributes to host defense via promotion of antimicrobial peptides. IL-17A regulates expression of several antimicrobial molecules including β-defensins, calgranulins (S100 proteins), and mucins [33–35, 39]. Defensins acting as natural antibiotics are potent antimicrobial peptides for host defense in the lung, skin, and gut [40, 41].

Systemically, IL-17A promotes expression of acute-phase protein lipocalin 2 [31, 32]. Lipocalin 2 binds to bacterial siderophores. Siderophores are iron-scavenging molecules that are necessary for the survival of bacteria and fungi. Lipocalin 2 binds siderophores and therefore inhibits the iron uptake by bacteria in the body [42]. It has been shown that lipocalin 2 is required for pulmonary defense against Klebsiella infection [43] and Escherichia coli in the intestine [42].

The importance of IL-17 cytokines in mucosal and cutaneous immunity in host defense was first indicated by a series of experiments in IL-17RA- or IL-17A-deficient mice [7, 44, 45]. Mice deficient in IL-17RA are highly susceptible to Klebsiella pneumoniae infection with a greater than 50 % fatality [7]. This is correlated with markedly decreased recruitment of neutrophils to the airway. Oropharyngeal candidiasis (OPC) is severe in IL-23- and IL-17RA-deficient mice, whereas IL-12-deficient mice showed low fungal burden and no overt infection [44]. This finding clearly indicates the critical role of IL-17A in mucosal immunity against Candida infection and that the IL-12 and Th1 pathway is less important. Furthermore, the source of IL-17A for this immunity is identified as γδT cells and Th17 cells [46]. Mice deficient in γδT cells develop exacerbations of skin Staphylococcus aureus infection with severely impaired neutrophil recruitment. This phenotype is similar to IL-17RA-deficient mice. Interestingly, a single dose of IL-17A could restore the impaired immunity in γδT cell deficiency. These data clearly define a critical role of IL-17A in skin defense against Staphylococcus aureus infection and the importance of the cellular source of IL-17A being the epidermal γδT cells [45].

The protective role of IL-17 cytokines in host defense in humans is categorically demonstrated in patients with genetic defect in pathways leading to defective production of IL-17 (Table 2.3). The disease severity in patients with gene mutations varies from mild focal infection to systemic and fatal conditions. In the context of blockade of the IL-17 pathway for therapy, perhaps the phenotype in patients with Aire deficiency more closely mimics the therapeutic blockade of IL-17 signaling. Indeed, patients with Aire deficiency produce autoantibodies against IL-17A, IL-17F, and IL-22 [47–50].