RORγt-Raftlin1 complex regulates the pathogenicity of Th17 cells and colonic inflammation

• Published in: Nature communications Vol. 14; no. 1; pp. 4972 - 15
• Main Authors: Singh, Amir Kumar, Kumar, Ritesh, Yin, Jianyi, Brooks II, John F., Kathania, Mahesh, Mukherjee, Sandip, Kumar, Jitendra, Conlon, Kevin P., Basrur, Venkatesha, Chen, Zhe, Han, Xianlin, Hooper, Lora V., Burstein, Ezra, Venuprasad, K.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 17.08.2023; Nature Publishing Group; Nature Portfolio
• Subjects: 14; 14/1; 42; 42/109; 631/250/1619/554/1898/1273; 631/250/256; 631/250/347; 692/699/1503; 82/58; 82/80; 82/83; Animal models; Antibodies; Bacteria; Cell culture; Citrobacter; Colon; Cytokines; Disease; Filamentous bacteria; Helper cells; Humanities and Social Sciences; Humans; Infections; Inflammation; Inflammatory bowel diseases; Interleukin 17; Intestine; Ligands; Lipids; Lymphocytes; Lymphocytes T; Medical research; multidisciplinary; Nuclear Receptor Subfamily 1, Group F, Member 3 - genetics; Pathogenicity; Pathogens; Phospholipids; Proteins; Science; Science (multidisciplinary); Th17 Cells; Virulence
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-023-40622-1

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. IL-17 secreting Th17 cells have established roles in numerous immune-pathologies but paradoxically are required homeostatically in the maintenance of the intestinal barrier. Here the authors establish Raftlin-1 in the recruitment of phospholipids that are linked to the emergence of pathogenic Th17 cells in animal models of bowel inflammation.