Presence, function and regulation of IL-17F-expressing human CD4+ T cells

The pro-inflammatory cytokine IL-17A has been implicated in the immunopathology of inflammatory arthritis. IL-17F bears 50% homology to IL-17A and has recently been suggested to play a role in inflammation. We investigated the induction and cytokine profile of IL-17F+ CD4+ T cells, and how IL-17F may contribute to inflammation. Upon culture of healthy donor CD4+ T cells with IL-1β, IL-23, anti-CD3 and anti-CD28 mAb, both IL-17A and IL-17F-expressing cells were detected. In comparison to IL-17A+IL-17F- CD4+ T cells, IL-17F+IL-17A- and IL-17A+IL-17F+ CD4+ T cells contained lower proportions of IL-10-expressing and GM-CSF-expressing cells and higher proportions of IFNγ-expressing cells. Titration of anti-CD28 mAb revealed that strong co-stimulation increased IL-17F+IL-17A- and IL-17A+IL-17F+ CD4+ T cell frequencies, whereas IL-17A+IL-17F- CD4+ T cell frequencies decreased. This was partly mediated via an IL-2-dependent mechanism. Addition of IL-17A, IL-17F and TNFα to synovial fibroblasts from patients with inflammatory arthritis resulted in significant production of IL-6 and IL-8, which was reduced to a larger extent by combined blockade of IL-17A and IL-17F than blockade of IL-17A alone. Our data indicate that IL-17A and IL-17F are differentially regulated upon T cell co-stimulation, and that dual blockade of IL-17A and IL-17F reduces inflammation more effectively than IL-17A blockade alone.