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The cytokines IL-17A and IL-17F have 50% amino-acid identity and bind the same receptor; however, their functional differences have remained obscure. Here we found that Il17f -/- mice resisted chemically induced colitis, but Il17a -/- mice did not, and that Il17f -/- CD45RB hi CD4 + T cells induced milder colitis in lymphocyte-deficient Rag2 -/- mice, accompanied by an increase in intestinal regulatory T cells (T reg cells). Clostridium cluster XIVa in colonic microbiota capable of inducing T reg cells was increased in both Il17f -/- mice and mice given transfer Il17f -/- T cells, due to decreased expression of a group of antimicrobial proteins. There was substantial production of IL-17F, but not of IL-17A, not only by naive T cells but also by various colon-resident cells under physiological conditions. Furthermore, antibody to IL-17F suppressed the development of colitis, but antibody to IL-17A did not. These observations suggest that IL-17F is an effective target for the treatment of colitis.

Interleukin-17 (IL-17)-producing γδ T (γδ17) cells have been implicated in inflammatory diseases, but the underlying pathogenic mechanisms remain unclear. Here, we show that both CD4(+) and γδ17 cells are required for the development of autoimmune arthritis in IL-1 receptor antagonist (IL-1Ra)-deficient mice. Specifically, activated CD4(+) T cells direct γδ T-cell infiltration by inducing CCL2 expression in joints. Furthermore, IL-17 reporter mice reveal that the Vγ6(+) subset of CCR2(+) γδ T cells preferentially produces IL-17 in inflamed joints. Importantly, because IL-1Ra normally suppresses IL-1R expression on γδ T cells, IL-1Ra-deficient mice exhibit elevated IL-1R expression on Vγ6(+) cells, which play a critical role in inducing them to produce IL-17. Our findings demonstrate a pathogenic mechanism in which adaptive and innate immunity induce an autoimmune disease in a coordinated manner.

Il1rn(-/-) mice spontaneously develop arthritis and aortitis by an autoimmune mechanism and also develop dermatitis by an autoinflammatory mechanism. Here, we show that Rag2(-/-)Il1rn(-/-) mice develop spontaneous colitis with high mortality, making a contrast to the suppression of arthritis in these mice. Enhanced IL-17A expression in group 3 innate lymphoid cells (ILC3s) was observed in the colon of Rag2(-/-)Il1rn(-/-) mice. IL-17A-deficiency prolonged the survival of Rag2(-/-)Il1rn(-/-) mice, suggesting a pathogenic role of this cytokine in the development of intestinal inflammation. Although IL-17A-producing T cells were increased in Il1rn(-/-) mice, these mice did not develop colitis, because CD4(+)Foxp3(+) regulatory T cell population was also expanded. Thus, excess IL-1 signaling and IL-1-induced IL-17A from ILC3s cause colitis in Rag2(-/-)Il1rn(-/-) mice in which Treg cells are absent. These observations suggest that the balance between IL-17A-producing cells and Treg cells is important to keep the immune homeostasis of the colon.

IL-1 is a proinflammatory cytokine consisting of two molecular species, IL-1alpha and IL-1beta, and IL-1R antagonist (gene: Il1rn) is the endogenous suppressor. Il1rn(-/-) mice spontaneously develop autoimmune diseases, such as arthritis and aortitis, and a dermatitis that histologically resembles human psoriasis. The pathogenic mechanisms underlying this dermatitis, however, remain to be elucidated. In this study, we demonstrated that the production of inflammatory cytokines and chemokines was enhanced at the site of inflammation. The development of dermatitis was completely suppressed in Tnfsf1a(-/-) but not in Il6(-/-) mice, similar to that observed in arthritis and aortitis. However, IL-17 deficiency did not affect the development of dermatitis at all, in clear contrast to that of arthritis and aortitis. Different from arthritis and aortitis, adoptive transfer of Il1rn(-/-) T cells did not induce dermatitis in the recipient SCID mice and skin lesions developed in Il1rn(-/-) SCID mice, indicating that T cells are not involved in the development of skin lesions. In support for this, bone marrow cell transplantation experiments showed that TNF produced by skin residential cells, but not bone marrow cell-derived cells, was important for the development of dermatitis. Furthermore, we showed that IL-1 directly enhanced TNF and chemokine expression in keratinocytes. These observations suggest that excess IL-1 signaling directly activates keratinocytes to produce TNF and chemokines, resulting in the development of psoriasis-like skin lesions without the involvement of autoimmunity in Il1rn(-/-) mice.

Dectin-2 (gene symbol Clec4n) is a C-type lectin expressed by dendritic cells (DCs) and macrophages. However, its functional roles and signaling mechanisms remain to be elucidated. Here, we generated Clec4n(-/-) mice and showed that this molecule is important for host defense against Candida albicans (C. albicans). Clec4n(-/-) DCs had virtually no fungal alpha-mannan-induced cytokine production. Dectin-2 signaling induced cytokines through an FcRgamma chain and Syk-CARD9-NF-kappaB-dependent signaling pathway without involvement of MAP kinases. The yeast form of C. albicans induced interleukin-1beta (IL-1beta) and IL-23 secretion in a Dectin-2-dependent manner. In contrast, cytokine production induced by the hyphal form was only partially dependent on this lectin. Both yeast and hyphae induced Th17 cell differentiation, in which Dectin-2, but not Dectin-1, was mainly involved. Because IL-17A-deficient mice were highly susceptible to systemic candida infection, this study suggests that Dectin-2 is important in host defense against C. albicans by inducing Th17 cell differentiation., (Copyright 2010 Elsevier Inc. All rights reserved.)

Interleukin-17A (IL-17A) is a cytokine produced by T helper 17 (Th17) cells and plays important roles in the development of inflammatory diseases. Although IL-17F is highly homologous to IL-17A and binds the same receptor, the functional roles of this molecule remain largely unknown. Here, we demonstrated with Il17a(-/-), Il17f(-/-), and Il17a(-/-)Il17f(-/-) mice that IL-17F played only marginal roles, if at all, in the development of delayed-type and contact hypersensitivities, autoimmune encephalomyelitis, collagen-induced arthritis, and arthritis in Il1rn(-/-) mice. In contrast, both IL-17F and IL-17A were involved in host defense against mucoepithelial infection by Staphylococcus aureus and Citrobacter rodentium. IL-17A was produced mainly in T cells, whereas IL-17F was produced in T cells, innate immune cells, and epithelial cells. Although only IL-17A efficiently induced cytokines in macrophages, both cytokines activated epithelial innate immune responses. These observations indicate that IL-17A and IL-17F have overlapping yet distinct roles in host immune and defense mechanisms.

IL-17 is a proinflammatory cytokine that activates T cells and other immune cells to produce a variety of cytokines, chemokines, and cell adhesion molecules. This cytokine is augmented in the sera and/or tissues of patients with contact dermatitis, asthma, and rheumatoid arthritis. We previously demonstrated that IL-17 is involved in the development of autoimmune arthritis and contact, delayed, and airway hypersensitivity in mice. As the expression of IL-17 is also augmented in multiple sclerosis, we examined the involvement of this cytokine in these diseases using IL-17(-/-) murine disease models. We found that the development of experimental autoimmune encephalomyelitis (EAE), the rodent model of multiple sclerosis, was significantly suppressed in IL-17(-/-) mice; these animals exhibited delayed onset, reduced maximum severity scores, ameliorated histological changes, and early recovery. T cell sensitization against myelin oligodendrocyte glycoprotein was reduced in IL-17(-/-) mice upon sensitization. The major producer of IL-17 upon treatment with myelin digodendrocyte glycopritein was CD4+ T cells rather than CD8+ T cells, and adoptive transfer of IL-17(-/-) CD4+ T cells inefficiently induced EAE in recipient mice. Notably, IL-17-producing T cells were increased in IFN-gamma(-/-) cells, while IFN-gamma-producing cells were increased in IL-17(-/-) cells, suggesting that IL-17 and IFN-gamma mutually regulate IFN-gamma and IL-17 production. These observations indicate that IL-17 rather than IFN-gamma plays a crucial role in the development of EAE.