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.

The interleukin-17 (IL-17) family consists of six family members (IL-17A–IL-17F) and all the corresponding receptors have been identified recently. This family is mainly involved in the host defense mechanisms against bacteria, fungi and helminth infection by inducing cytokines and chemokines, recruiting neutrophils, inducing anti-microbial proteins and modifying T-helper cell differentiation. IL-17A and some other family cytokines are also involved in the development of psoriasis, psoriatic arthritis and ankylosing spondylitis by inducing inflammatory cytokines and chemokines, and antibodies against IL-17A as well as the receptor IL-17RA are being successfully used for the treatment of these diseases. Involvement in the development of inflammatory bowel disease, multiple sclerosis, rheumatoid arthritis and tumors has also been suggested in animal disease models. In this review, we will briefly review the mechanisms by which IL-17 cytokines are involved in the development of these diseases and discuss possible treatment of inflammatory diseases by targeting IL-17 family members.

Introduction: Chemokines and their receptors are potential therapeutic targets in rheumatoid arthritis (RA). Among these, several studies suggested the involvement of CXC chemokine 4 (CXCR4) and its ligand CXC ligand 12 (SDF-1) in RA pathogenesis. However, the role of these molecules in T-cell function is not known completely because of embryonic lethality of Cxcr4- and Cxcl12-deficient mice. In this report, we generated T cell-specific Cxcr4-deficient mice and showed that the CXCR4 in T cells is important for the development of collagen-induced arthritis (CIA). Methods: T cell-specific Cxcr4-deficient mice were generated by using the Cre-loxP system. Mice harboring loxP sites flanking exon 2 of the Cxcr4gene (Cxcr4 ^flox/flox ) were generated by homologous recombination and crossed with Cre transgenic mice expressing Cre recombinase under the control of Lck promoter (Cxcr4 ^+/+ /Lck-Cremice) to generate T cell-specific Cxcr4-deficient mice (Cxcr4 ^flox/flox /Lck-Cre mice). CIA was induced by immunization with chicken type II collagen and Complete Freund's Adjuvant (CFA). Results: The incidence, but not the severity, of CIA was significantly reduced in Cxcr4 ^flox/flox /Lck-Cre mice compared with Cxcr4 ^+/+ /Lck-Cre mice. We found that the expression of CXCR4 was enhanced in activated T cells, and the migration of Cxcr4-deficient T cells toward SDF-1 was severely impaired. However, antibody production, cellular proliferative response, and cytokine production on treatment with type II collagen (IIC) were normal in these knockout mice, suggesting that CXCR4 is not involved in T-helper functions. Interestingly, the proportion of CXCR4-expressing T cells was much increased in affected joints compared with that in draining lymph nodes in CIA-induced mice, and distribution of Cxcr4 ^flox/flox /Lck-Cre mouse-derived T cells into affected joints was suppressed compared with that in Cxcr4 ^+/+ /Lck-Cre T cells. Conclusions: These results indicate that CXCR4 expression in T cells is important for the development of CIA, by recruiting activated T cells toward inflammatory sites, and suggest that CXCR4 is a good target for the treatment of RA in humans.

Dendritic cell immunoreceptor (DCIR) is a C-type lectin receptor mainly expressed in DCs. Dcir^−/− mice spontaneously develop autoimmune enthesitis and ankylosis accompanied by fibrocartilage proliferation and ectopic ossification. However, the mechanisms of new bone/cartilage formation in Dcir^−/− mice remain to be elucidated. In this study, we show that DCIR maintains bone homeostasis by regulating IFN-γ production under pathophysiological conditions. DCIR deficiency increased bone volume in femurs and caused aberrant ossification in joints, whereas these symptoms were abolished in Rag2^−/−Dcir^−/− mice. IFN-γ–producing T cells accumulated in lymph nodes and joints of Dcir^−/− mice, and purified Dcir^−/− DCs enhanced IFN-γ⁺ T cell differentiation. The ankylotic changes and bone volume increase were suppressed in the absence of IFN-γ. Thus, IFN-γ is a positive chondrogenic and osteoblastogenic factor, and DCIR is a crucial regulator of bone metabolism; consequently, both factors are potential targets for therapies directed against bone metabolic diseases.