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 P. Conlon, Venkatesha Basrur, Zhe Chen, Xianlin Han, Lora V. Hooper, Ezra Burstein and K. Venuprasad ()
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Amir Kumar Singh: UT Southwestern Medical Center
Ritesh Kumar: UT Southwestern Medical Center
Jianyi Yin: UT Southwestern Medical Center
John F. Brooks: UT Southwestern Medical Center
Mahesh Kathania: UT Southwestern Medical Center
Sandip Mukherjee: UT Southwestern Medical Center
Jitendra Kumar: UT Southwestern Medical Center
Kevin P. Conlon: University of Michigan
Venkatesha Basrur: University of Michigan
Zhe Chen: UT Southwestern Medical Center
Xianlin Han: University of Texas Health Science Center at San Antonio
Lora V. Hooper: UT Southwestern Medical Center
Ezra Burstein: UT Southwestern Medical Center
K. Venuprasad: UT Southwestern Medical Center

Nature Communications, 2023, vol. 14, issue 1, 1-15

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-40622-1

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