Regulation of RORγt in Th17-mediated inflammation

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ABSTRACT Th17 cells that produce IL-17 are pathogenic in many diseases, including inflammatory bowel disease(IBD), but are paradoxically essential for maintaining the integrity of the intestinal barrier in a non-inflammatory manner. However, the intracellular mechanisms that regulate distinct transcriptional profiles and functional diversity of Th17 cells remain unclear. ROR-γt, the transcription factor for IL-17, is expressed in both pathogenic and nonpathogenic Th17 cells. ROR-γt is composed of a DNA-binding domain and a ligand-binding domain (LBD). The LBD contains the activation function 2 (AF2) region responsible for recruiting coactivator and corepressor proteins. ROR-γt is often called 'orphan nuclear receptor' because its natural ligands are unknown/unclear. Our preliminary studies have identified Raftlin1, a lipid raft protein, as a ROR-γt interacting protein. Raftlin1 forms a complex with ROR-γt by binding to the AF2 domain via its conserved 'LLNSL' motif. By liquid chromatography coupled to mass spectrometry (LC-MS), we have identified that a few lipid species [lysophosphatidylethanolamines(LPEs), Phosphatidylserines (PSs), and Phosphatidylcholines (PCs)] binds to Raftlin1 and ROR-γt. Based on these novel findings, we hypothesize that Raftlin1 acts as an adaptor for ROR-γt and recruits its natural lipid ligands, and promotes the pathogenicity of Th17. We will test this hypothesis under two aims. Aim1 will investigate the function of ROR-γt-Raftlin1 complex in gastrointestinal inflammation, and Aim 2, will determine the mechanism by which ROR-γt-Raftlin1 complex regulates the pathogenicity of Th17 cells. With the completion of these studies, we expect to (1) establish the role of ROR-γt-Raftlin1 complex in driving the pathogenicity of Th17 cells and (2) explore the function of LPEs as the natural ligands of ROR-γt in pathogenic Th7 cells.