RORγt-Raftlin1 complex regulates the pathogenicity of Th17 cells and colonic inflammation
Amir Kumar Singh, Ritesh Kumar, Jianyi Yin, John F. Brooks, Mahesh Kathania, Sandip Mukherjee, Jitendra Kumar, Kevin Conlon, Venkatesha Basrur, Zhe Chen, Xianlin Han, Lora V. Hooper, Ezra Burstein, K. Venuprasad
Abstract
Th17 cells that produce Interleukin IL-17 are pathogenic in many human diseases, including inflammatory bowel disease, but are, paradoxically, essential for maintaining the integrity of the intestinal barrier in a non-inflammatory state. However, the intracellular mechanisms that regulate distinct transcriptional profiles and functional diversity of Th17 cells remain unclear. Here we show Raftlin1, a lipid raft protein, specifically upregulates and forms a complex with RORγt in pathogenic Th17 cells. Disruption of the RORγt-Raftlin1 complex results in the reduction of pathogenic Th17 cells in response to Citrobacter rodentium; however, there is no effect on nonpathogenic Th17 cells in response to commensal segmented filamentous bacteria. Mechanistically, we show that Raftlin1 recruits distinct phospholipids to RORγt and promotes the pathogenicity of Th17 cells. Thus, we have identified a mechanism that drives the pathogenic function of Th17 cells, which could provide a platform for advanced therapeutic strategies to dampen Th17-mediated inflammatory diseases.