Tu123 - IL-23 Signaling Induces Autoimmune Disease Genes in Mucosal-associated Invariant T (MAIT) Cells

Genome-wide association studies and mouse models of autoimmune disease have demonstrated an important role of the IL-23 signaling pathway in the pathogenesis of psoriasis, Crohn’s disease (CD) and axial spondyloarthritis (axSpA). This notion has been validated in the clinics by the successful treatment of psoriasis and CD with IL-23 blockers. However, despite a strong genetic association and pre-clinical models arguing in favor of IL-23 as a valid pharmaceutical target, IL-23-blockers failed in axSpA. This unexpected finding raised questions about the role of IL-23 in the pathogenesis of axSpA and psoriasis.

The goal of this project is to determine which human T cell populations can respond to IL-23 and how IL-23 signaling regulates immune functions.

We found that mucosal-associated invariant T (MAIT) cells expressed higher level of the IL-23R mRNA and protein than other immune cell populations. To better define the effects of IL-23 on MAIT cells, we used a MHC related molecule 1 (MR1) tetramer presenting the 5-OP-RU antigen. Compared to anti-CD3/CD28 T cell stimulation, we observed that the tetramer induced specifically MAIT cell activation and proliferation. Activation of MAIT cells in the presence of IL-23 enhanced secretion of several cytotoxic molecules, however, did not increase IL-17A/F production by these cells. Of note, disease and KEGG pathway overrepresentation analysis of RNA-seq data revealed significant enrichment of autoimmune disease genes in MAIT cells cultured in the presence of IL-23. Ongoing single-cell analyses investigate the contribution of these IL-23-induced genes to pathogenic functions of MAIT cells.