Interleukin-23 receptor signaling drives inflammatory Th17 cell state via modulation of chromatin remodeling and nuclear hormone receptor activity 3404

Abstract Description Interleukin-23 receptor (IL-23R) signaling drives pro-inflammatory IL-17-producing (Th17) cells, key contributors to autoimmune tissue inflammation. However, the mechanisms by which IL-23 mediates its effects in Th17 cells remain unclear. Transcriptomic analyses of IL-23-treated Th17 cells have identified an inflammatory gene signature, but these findings alone do not explain how IL-23 promotes Th17 pathogenicity, suggesting additional regulatory mechanisms. To investigate, we performed integrated phosphoproteomic and transcriptomic analyses of human T cells activated by IL-23 or IL-12. This approach uncovered two IL-23R-specific targets: a chromatin remodeling protein and a nuclear hormone receptor. IL-23R activation enhanced the chromatin remodeling protein, upregulating RORγt expression and reinforcing Th17 lineage commitment. Conversely, IL-23R signaling suppressed the expression and phosphorylation of the hormone receptor, sustaining gene programs associated with a homeostatic Th17 state. These findings identify a novel IL-23R-regulated pathway involving chromatin remodeling and hormone receptor modulation, revealing new mechanisms that influence Th17 cell stability and inflammatory potential. This pathway offers promising therapeutic targets for mitigating Th17-driven autoimmune inflammation. Topic Categories Cytokines and Chemokines and Their Receptors (CCR)