Proinflammatory Cytokine Environments Can Drive Interleukin-17 Overexpression by γ/δ T Cells in Systemic Juvenile Idiopathic Arthritis

Objective. Systemic-onset juvenile idiopathic arthritis (JIA) is speculated to follow a biphasic course, with an initial systemic disease phase driven by innate immune mechanisms and interleukin-1 beta (IL-1 beta) as a key cytokine and a second chronic arthritic phase thatmay be dominated by adaptive immunity and cytokines such as IL-17A. Although a recent mouse model points to a critical role of IL-17-expressing gamma/delta T cells in disease pathology, in humans, both the prevalence of IL-17 and the role of IL-17producing cells are still unclear. Methods. Serum samples from systemic JIA patients and healthy pediatric controls were analyzed for the levels of IL-17A and related cytokines. Whole blood samples were studied for cellular expression of IL-17 and interferon-g (IFNg). CD41 and gamma/delta T cells isolated from the patients and controls were assayed for cytokine secretion in different culture systems. Results. IL-17A was prevalent in sera from patients with active systemic JIA, while both ex vivo and in vitro experiments revealed that gamma/delta T cells overexpressed this cytokine. This was not seen with CD41 T cells, which expressed strikingly low levels of IFNg. Therapeutic IL-1 blockade was associated with partial normalization of both cytokine expression phenotypes. Furthermore, culturing healthy donor gamma/delta T cells in serum from systemic JIA patients or in medium spiked with IL-1 beta, IL-18, and S100A12 induced IL-17 overexpression at levels similar to those observed in the patients' cells. Conclusion. A systemic JIA cytokine environment may prime gamma/delta T cells in particular for IL-17A overexpression. Thus, our observations in systemic JIA patients strongly support a pathophysiologic role of these cells, as proposed by the recent murine model.