In fact, recent studies have led to the realization that Th17 cells may represent a heterogeneous group of IL-17-producing cells that vary in their expression profile, effector functions, and pathogenicity GDC 0449 [10, 11]. The relative abundance of TGF-β and IL-23 has emerged as a major skewing factor between “classical” and “alternative” Th17 cells. Classical Th17 cells arise in an environment with relatively low amounts of IL-23 and appear to have a more regulatory phenotype,

with production of cytokines such as IL-10 and IL-21, than the more pathogenic alternative Th17 cells, which secrete IFN-γ and GM-CSF and are generated in the presence of IL-23 (reviewed in [12]). Although Th17 cells have been the focus of much attention in the past few years, mainly because of their involvement in autoimmune diseases, they are not the sole producers of IL-17. Indeed, CD4−CD8− double-negative (DN) T cells have been shown to secrete large amounts of IL-17 [13], and much of the IL-17 secreted during early inflammatory responses, for example following microbial infection, is produced by innate immune cells as discussed by Mills

and colleagues in an accompanying article in this Th17 review series in the European Journal of Immunology [14]. Such cells include γδT cells, lymphoid-tissue inducer-like cells, invariant natural killer (NK) T cells, NK cells, mTOR inhibitor and neutrophils (reviewed in [15]). Most of these cell types can be found in mucosal and epithelial barriers, for example in the gut, lungs, and skin, and have an important role in tissue surveillance. Mast cells have also been reported to secrete IL-17 in synovium from individuals with rheumatoid arthritis and in psoriatic lesions [16-18]. Emerging data suggest IL-17-producing cells may be central to the pathogenesis of systemic autoimmune diseases. Increased plasma levels of IL-17, as

well as an increased frequency of however IL-17-producing T cells, have been reported in patients with SLE and have been shown to correlate with disease activity in some studies [13, 19-23]. Both Th17 and DN T-cell populations are expanded in patients with SLE as compared with healthy individuals. DN T cells were already known to be positively associated with lupus nephritis and to participate in the induction of anti-DNA autoantibody production some 20 years ago [24]; however, interest in their role in SLE pathogenesis has recently been renewed when they were found to be major producers of IL-17 in SLE and to infiltrate kidneys in patients with lupus nephritis [13]. Indeed, IL-17-producing T cells have been detected in the main target organs in SLE, such as skin, kidneys, and lungs, suggesting that IL-17 may play a role in local inflammation and resulting tissue damage [20, 25, 26]. Further supporting the presence of a Th17-biased environment in patients with SLE, increased plasma levels of IL-6, a crucial differentiating factor for Th17 cells, as well as IL-21, a Th17 cytokine, have been observed in such patients [22, 27-29].