RORγt-Raftlin1 complex regulates the pathogenicity of Th17 cells and colonic inflammation
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 d...
| Main Authors: | , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2023-08-01
|
| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-023-40622-1 |
| _version_ | 1797558543264514048 |
|---|---|
| author | Amir Kumar Singh Ritesh Kumar Jianyi Yin John F. Brooks II Mahesh Kathania Sandip Mukherjee Jitendra Kumar Kevin P. Conlon Venkatesha Basrur Zhe Chen Xianlin Han Lora V. Hooper Ezra Burstein K. Venuprasad |
| author_facet | Amir Kumar Singh Ritesh Kumar Jianyi Yin John F. Brooks II Mahesh Kathania Sandip Mukherjee Jitendra Kumar Kevin P. Conlon Venkatesha Basrur Zhe Chen Xianlin Han Lora V. Hooper Ezra Burstein K. Venuprasad |
| author_sort | Amir Kumar Singh |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-10T17:31:57Z |
| format | Article |
| id | doaj.art-befedf1f83644092980fd717763deaa0 |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-03-10T17:31:57Z |
| publishDate | 2023-08-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-befedf1f83644092980fd717763deaa02023-11-20T09:59:37ZengNature PortfolioNature Communications2041-17232023-08-0114111510.1038/s41467-023-40622-1RORγt-Raftlin1 complex regulates the pathogenicity of Th17 cells and colonic inflammationAmir Kumar Singh0Ritesh Kumar1Jianyi Yin2John F. Brooks II3Mahesh Kathania4Sandip Mukherjee5Jitendra Kumar6Kevin P. Conlon7Venkatesha Basrur8Zhe Chen9Xianlin Han10Lora V. Hooper11Ezra Burstein12K. Venuprasad13Department of Internal Medicine, UT Southwestern Medical CenterDepartment of Internal Medicine, UT Southwestern Medical CenterDepartment of Internal Medicine, UT Southwestern Medical CenterDepartment of Immunology, UT Southwestern Medical CenterDepartment of Internal Medicine, UT Southwestern Medical CenterDepartment of Internal Medicine, UT Southwestern Medical CenterDepartment of Internal Medicine, UT Southwestern Medical CenterDepartment of Pathology, University of MichiganDepartment of Pathology, University of MichiganDepartment of Biophysics, UT Southwestern Medical CenterUniversity of Texas Health Science Center at San AntonioDepartment of Immunology, UT Southwestern Medical CenterDepartment of Internal Medicine, UT Southwestern Medical CenterDepartment of Internal Medicine, UT Southwestern Medical CenterAbstract 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.https://doi.org/10.1038/s41467-023-40622-1 |
| spellingShingle | Amir Kumar Singh Ritesh Kumar Jianyi Yin John F. Brooks II Mahesh Kathania Sandip Mukherjee Jitendra Kumar Kevin P. Conlon Venkatesha Basrur Zhe Chen Xianlin Han Lora V. Hooper Ezra Burstein K. Venuprasad RORγt-Raftlin1 complex regulates the pathogenicity of Th17 cells and colonic inflammation Nature Communications |
| title | RORγt-Raftlin1 complex regulates the pathogenicity of Th17 cells and colonic inflammation |
| title_full | RORγt-Raftlin1 complex regulates the pathogenicity of Th17 cells and colonic inflammation |
| title_fullStr | RORγt-Raftlin1 complex regulates the pathogenicity of Th17 cells and colonic inflammation |
| title_full_unstemmed | RORγt-Raftlin1 complex regulates the pathogenicity of Th17 cells and colonic inflammation |
| title_short | RORγt-Raftlin1 complex regulates the pathogenicity of Th17 cells and colonic inflammation |
| title_sort | rorγt raftlin1 complex regulates the pathogenicity of th17 cells and colonic inflammation |
| url | https://doi.org/10.1038/s41467-023-40622-1 |
| work_keys_str_mv | AT amirkumarsingh rorgtraftlin1complexregulatesthepathogenicityofth17cellsandcolonicinflammation AT riteshkumar rorgtraftlin1complexregulatesthepathogenicityofth17cellsandcolonicinflammation AT jianyiyin rorgtraftlin1complexregulatesthepathogenicityofth17cellsandcolonicinflammation AT johnfbrooksii rorgtraftlin1complexregulatesthepathogenicityofth17cellsandcolonicinflammation AT maheshkathania rorgtraftlin1complexregulatesthepathogenicityofth17cellsandcolonicinflammation AT sandipmukherjee rorgtraftlin1complexregulatesthepathogenicityofth17cellsandcolonicinflammation AT jitendrakumar rorgtraftlin1complexregulatesthepathogenicityofth17cellsandcolonicinflammation AT kevinpconlon rorgtraftlin1complexregulatesthepathogenicityofth17cellsandcolonicinflammation AT venkateshabasrur rorgtraftlin1complexregulatesthepathogenicityofth17cellsandcolonicinflammation AT zhechen rorgtraftlin1complexregulatesthepathogenicityofth17cellsandcolonicinflammation AT xianlinhan rorgtraftlin1complexregulatesthepathogenicityofth17cellsandcolonicinflammation AT loravhooper rorgtraftlin1complexregulatesthepathogenicityofth17cellsandcolonicinflammation AT ezraburstein rorgtraftlin1complexregulatesthepathogenicityofth17cellsandcolonicinflammation AT kvenuprasad rorgtraftlin1complexregulatesthepathogenicityofth17cellsandcolonicinflammation |