P089 Mucosal-associated invariant T (MAIT)-cell-derived IL-17A and IL-17F production is IL-23-independent and biased towards IL-17F
Authors: S Cole, A Maroof
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Career situation of first and presenting author</h3> Young investigator. <h3>Introduction</h3> The requirement for IL-23 in driving IL-17A and IL-17F production in humans is incompletely understood. Preclinical data support IL-17F, together with IL-17A, as a key driver of chronic tissue inflammation.<sup>1</sup> MAIT cells, an innate T-cell population, uniformly express RORγt but only a minority have been shown to produce IL-17A.<sup>2</sup> Dysregulation in frequency and function of MAIT cells has been associated with IL-17A-mediated inflammatory diseases, including PsA and AS.<sup>3 4</sup> IL-17F production in MAIT cells remains largely unexplored. <h3>Objectives</h3> To explore the importance of IL-23 signalling in MAIT-cell-derived IL-17A and IL-17F production, examine the presence of MAIT cells in psoriatic lesional skin and assess the contribution of MAIT-cell-derived IL-17A and IL-17F using <i>in vitro</i> models of skin inflammation. <h3>Methods</h3> IL-17A and IL-17F production by MAIT cells was assessed by flow cytometry, ELISA, qPCR and CyTOF upon activation by anti-CD3/CD28 or fixed <i>E. coli</i> via MR1–presented riboflavin metabolites, ±recombinant cytokines or an IL-23-neutralising antibody. RNAscope was utilised to observe MAIT cells in psoriatic lesional skin. MAIT cell supernatant, generated by FACS sorting, was cultured with normal human dermal fibroblasts (NHDFs) in the presence of IL-17-isoform-specific antibodies, including bimekizumab, a monoclonal antibody that potently and selectively neutralises both IL-17A and IL-17F. <h3>Results</h3> Optimal MAIT cell IL-17A and IL-17F production occurred upon T-cell receptor triggering with IL-12 and IL-18, independently of IL-23. IL-17F expression was greater at both gene and protein levels than IL-17A. The kinetics and threshold of activation for IL-17A and IL-17F suggest tighter regulation compared with other inflammatory cytokines, including IFNγ and TNF. Optimal MAIT cell IL-17A and IL-17F production requires monocytes, which contribute to IL-12 production upon IL-18 stimulation. MAIT cells were abundant in psoriatic lesional skin. NHDFs cultured with supernatant generated from activated MAIT cells produced inflammatory mediators IL-6, IL-8 and CCL2, which were reduced upon inhibition of either IL–17A or IL-17F, with optimal suppression achieved following dual neutralisation with bimekizumab. <h3>Conclusions</h3> IL-17A and IL-17F can be produced from MAIT cells independently of IL-23, and contribute to inflammatory responses in NHDFs. These results support dual neutralisation of IL-17A and IL-17F as a complete and targeted approach to supress IL–17–driven inflammatory responses. <h3>References</h3> Glatt. <i>Ann Rheum Dis</i> 2018;77:523–32. Dusseaux. <i>Blood</i> 2011;117:1250–59. Menon. <i>Arthritis Rheumatol</i> 2014;66:1272–81 Gracey. <i>Ann Rheum Dis</i> 2016;75:2124–32. <h3>Acknowledgements</h3> Funded by UCB Pharma. The authors acknowledge Catherine Simpson for FACS sorting and Remi Okoye for RNAscope. <h3>Disclosure of Interest</h3> S. Cole Employee of: UCB Pharma, A. Maroof Employee of: UCB Pharma (also has a patent pending).