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-¿t, the transcription factor for IL-17, is expressed in both pathogenic and
nonpathogenic Th17 cells. ROR-¿t 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-¿t 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-¿t interacting protein. Raftlin1 forms a
complex with ROR-¿t 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-¿t. Based on these novel findings, we hypothesize that Raftlin1 acts as an adaptor for ROR-¿t
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-¿t-Raftlin1 complex in gastrointestinal inflammation, and Aim
2, will determine the mechanism by which ROR-¿t-Raftlin1 complex regulates the pathogenicity of Th17 cells.
With the completion of these studies, we expect to (1) establish the role of ROR-¿t-Raftlin1 complex in driving
the pathogenicity of Th17 cells and (2) explore the function of LPEs as the natural ligands of ROR-¿t in pathogenic
Th7 cells.