Probes for IL-17A

IL-17A has a pivotal pathogenic role in several immune-mediated inflammatory diseases. Despite sharing 50% sequence homology with IL-17A, the role of IL-17F remains less clear. Recent clinical findings suggest that dual inhibition of IL-17A and IL-17F in psoriatic disease is more efficacious than IL-17A inhibition alone, positing a pathogenic role for IL-17F.To characterize the regulation of IL-17A and IL-17F in psoriatic disease.Using both in vitro systems and lesional skin tissue from patients, we interrogated the chromosomal, transcriptional and protein expression landscape of IL-17A+ and IL-17F+ Th17 cells. Alongside established assays such as single-cell RNA sequencing, we developed a novel cytokine-capture technique that was combined with ChIP-seq and RNA-seq.We confirm a preferential elevation of IL-17F over IL-17A in psoriatic disease, and show that expression of each isoform predominantly occurs in distinct cell populations. The expression of both IL-17A and IL-17F exhibited a high degree of plasticity, with the balance between the two isoforms influenced by pro-inflammatory signaling and by anti-inflammatory drugs such as methylprednisolone. This plasticity was reflected in a broad H3K4me3 region at the IL17A-F locus, while opposing effects of STAT5/IL-2 signaling were observed for each of the two genes. Functionally, higher IL17F expression was linked to greater cell proliferation.Our data suggest there are key differences in the regulation of IL-17A and IL-17F in psoriatic disease, leading to distinct inflammatory cell populations. As such, we propose that both IL-17A and IL-17F neutralization may be required to maximally inhibit IL-17-driven pathology.