Interleukin 17 (IL-17) has been linked to autoimmune diseases, although its regulation and function have remained unclear. Here we have evaluated in vitro and in vivo the requirements for the differentiation of naive CD4 T cells into effector T helper cells that produce IL-17. This process required the costimulatory molecules CD28 and ICOS but was independent of the cytokines and transcription factors required for T helper type 1 or type 2 differentiation. Furthermore, both IL-4 and interferon-γ negatively regulated T helper cell production of IL-17 in the effector phase. In vivo, antibody to IL-17 inhibited chemokine expression in the brain during experimental autoimmune encephalomyelitis, whereas overexpression of IL-17 in lung epithelium caused chemokine production and leukocyte infiltration. Thus, IL-17 expression characterizes a unique T helper lineage that regulates tissue inflammation.

A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17

Since its conception two decades ago, the Th1-Th2 paradigm has provided a framework for understanding T cell biology and the interplay of innate and adaptive immunity. Naive T cells differentiate into effector T cells with enhanced functional potential for orchestrating pathogen clearance largely under the guidance of cytokines produced by cells of the innate immune system that have been activated by recognition of those pathogens. This secondary education of post-thymic T cells provides a mechanism for appropriately matching adaptive immunity to frontline cues of the innate immune system. Owing in part to the rapid identification of novel cytokines of the IL-17 and IL-12 families using database searches, the factors that specify differentiation of a new effector T cell lineage-Th17-have now been identified, providing a new arm of adaptive immunity and presenting a unifying model that can explain many heretofore confusing aspects of immune regulation, immune pathogenesis, and host defense.

IL-17 Family Cytokines and the Expanding Diversity of Effector T Cell Lineages

IL-17 is a newly discovered T cell-derived cytokine whose role in osteoclast development has not been fully elucidated. Treatment of cocultures of mouse hemopoietic cells and primary osteoblasts with recombinant human IL-17 induced the formation of multinucleated cells, which satisfied major criteria of osteoclasts, including tartrate-resistant acid phosphatase activity, calcitonin receptors, and pit formation on dentine slices. Direct interaction between osteoclast progenitors and osteoblasts was required for IL-17-induced osteoclastogenesis, which was completely inhibited by adding indomethacin or NS398, a selective inhibitor of cyclooxgenase-2 (COX-2). Adding IL-17 increased prostaglandin E2 (PGE2) synthesis in cocultures of bone marrow cells and osteoblasts and in single cultures of osteoblasts, but not in single cultures of bone marrow cells. In addition, IL-17 dose-dependently induced expression of osteoclast differentiation factor (ODF) mRNA in osteoblasts. ODF is a membrane-associated protein that transduces an essential signal(s) to osteoclast progenitors for differentiation into osteoclasts. Osteoclastogenesis inhibitory factor (OCIF), a decoy receptor of ODF, completely inhibited IL-17-induced osteoclast differentiation in the cocultures. Levels of IL-17 in synovial fluids were significantly higher in rheumatoid arthritis (RA) patients than osteoarthritis (OA) patients. Anti-IL-17 antibody significantly inhibited osteoclast formation induced by culture media of RA synovial tissues. These findings suggest that IL-17 first acts on osteoblasts, which stimulates both COX-2-dependent PGE2 synthesis and ODF gene expression, which in turn induce differentiation of osteoclast progenitors into mature osteoclasts, and that IL-17 is a crucial cytokine for osteoclastic bone resorption in RA patients.

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IL-17 in synovial fluids from patients with rheumatoid arthritis is a potent stimulator of osteoclastogenesis

Background and aim: Interleukin (IL) 17 is a cytokine which exerts strong proinflammatory activities. In this study we evaluated changes in IL-17 expression in the inflamed mucosa and in the serum of patients with inflammatory bowel disease (IBD).

Methods: Tissue samples were obtained endoscopically or surgically from patients with ulcerative colitis (UC) (n=20), Crohn’s disease (CD) (n=20), infectious colitis (n=5), ischaemic colitis (n=8), and normal colorectal tissues (n=15). IL-17 expression was evaluated by a standard immunohistochemical procedure. Serum IL-17 levels were determined by ELISA. IL-17 mRNA expression was analysed by reverse transcriptase-polymerase chain reaction.

Results: IL-17 expression was not detected in samples from normal colonic mucosa, infectious colitis, or ischaemic colitis. In the inflamed mucosa of active UC and CD patients, IL-17 expression was clearly detectable in CD3+ T cells or CD68+ monocytes/macrophages. The average number of IL-17+ cells was significantly increased in active UC and CD patients compared with inactive patients. IL-17 mRNA expression was not detected in normal mucosa but was detectable in the mucosa from active UC and CD patients. IL-17 was not detected in the sera from normal individuals, infectious colitis, or ischaemic colitis patients but IL-17 levels were significantly elevated in IBD patients.

Conclusions: IL-17 expression in the mucosa and serum was increased in IBD patients. It is likely that IL-17 expression in IBD may be associated with altered immune and inflammatory responses in the intestinal mucosa.

https://gut.bmj.com/content/gutjnl/52/1/65.full.pdf

Increased expression of interleukin 17 in inflammatory bowel disease.

Protein release from alginate matrices.

A cDNA encoding human IL-17 (hIL-17) was cloned from a CD4+ T cell library. The predicted 155-amino acids sequence contains an N-terminal signal peptide and exhibits 72% amino acid identity with HVS13, an open reading frame from a T-lymphotropic Herpesvirus saimiri, and 63% with murine CTLA8. High levels of hIL-17 were induced from primary peripheral blood CD4+ T cells upon stimulation. When expressed in CV1/EBNA cells, recombinant hIL-17 was secreted in both glycosylated and nonglycosylated forms. A hIL-17.Fc fusion protein and supernatants from cells transfected with hIL-17 induced IL-6 and IL-8 production and enhanced the surface expression of the intracellular adhesion molecule-1 (ICAM-1) in human fibroblasts.

Human IL-17: a novel cytokine derived from T cells.

The Epstein-Barr virus BZLF2 gene encodes a glycoprotein that associates with gH and gL and facilitates the infection of B lymphocytes. In order to determine whether the BZLF2 protein recognizes a B-cell-specific surface antigen, a soluble protein containing the extracellular portion of the BZLF2 protein linked to the Fc portion of human immunoglobulin G1 (BZLF2.Fc) was expressed from mammalian cells. BZLF2.Fc was used in an expression cloning system and found to bind to a beta-chain allele of the HLA-DR locus of the class II major histocompatibility complex (MHC). Analysis of amino- and carboxy-terminal deletion mutants of the BZLF2.Fc protein indicated that the first 90 amino acids of BZLF2.Fc are not required for HLA-DR beta-chain recognition. Site-directed mutagenesis of an HLA-DR beta-chain cDNA and subsequent immunoprecipitation of expressed mutant beta-chain proteins using BZLF2.Fc indicated that the beta1 domain, which participates in the formation of peptide binding pockets, is required for BZLF2.Fc recognition. The addition of BZLF2.Fc to sensitized peripheral blood mononuclear cells in vitro abolished their proliferative response to antigen and inhibited cytokine-dependent cytotoxic T-cell generation in mixed lymphocyte cultures. Flow-cytometric analysis of Akata cells induced to express late Epstein-Barr virus antigens indicated that expression of BZLF2 did not result in reduced surface expression levels of MHC class II. The ability of BZLF2.Fc to bind to the HLA-DR beta chain suggests that the BZLF2 protein may interact with MHC class II on the surfaces of B cells.

D. Ulrich

Papers

Human IL-17: a novel cytokine derived from T cells.

The extracellular domain of the Epstein-Barr virus BZLF2 protein binds the HLA-DR beta chain and inhibits antigen presentation.