title: Tiam1/Rac1 complex controls Il17a transcription and autoimmunity.
abstract: RORγt is a master transcription factor of Th17 cells and considered as a promising drug target for the treatment of autoimmune diseases. Here, we show the guanine nucleotide exchange factor, Tiam1, and its cognate Rho-family G protein, Rac1, regulate interleukin (IL)17A transcription and autoimmunity. Whereas Tiam1 genetic deficiency weakens IL-17A expression partially and inhibits the development of experimental autoimmune encephalomyelitis (EAE), deletion of Rac1 in T cells exhibits more robust effects on Th17 cells and EAE. We demonstrate Tiam1 and Rac1 form a complex with RORγt in the nuclear compartment of Th17 cells, and together bind and activate the Il17 promoter. The clinical relevance of these findings is emphasized by pharmacological targeting of Rac1 that suppresses both murine and human Th17 cells as well as EAE. Thus, our findings highlight a regulatory pathway of Tiam1/Rac1 in Th17 cells and suggest that it may be a therapeutic target in multiple sclerosis.
authors.affiliation: Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Ahmed T
authors.initials: AT
authors.lastname: Kurdi
authors.affiliation: Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Ribal
authors.initials: R
authors.lastname: Bassil
authors.affiliation: Program in Translational NeuroPsychiatric Genomics, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Broad Institute at Harvard University and MIT, Boston, Massachusetts 02115, USA.
authors.forename: Marta
authors.initials: M
authors.lastname: Olah
authors.affiliation: Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Chuan
authors.initials: C
authors.lastname: Wu
authors.affiliation: Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Sheng
authors.initials: S
authors.lastname: Xiao
authors.affiliation: Program in Translational NeuroPsychiatric Genomics, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Broad Institute at Harvard University and MIT, Boston, Massachusetts 02115, USA.
authors.forename: Mariko
authors.initials: M
authors.lastname: Taga
authors.affiliation: Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Frangieh
authors.affiliation: Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Buttrick
authors.affiliation: Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: William
authors.initials: W
authors.lastname: Orent
authors.affiliation: Program in Translational NeuroPsychiatric Genomics, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Broad Institute at Harvard University and MIT, Boston, Massachusetts 02115, USA.
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Bradshaw
authors.affiliation: Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.|Abu Haidar Neuroscience Institute, American University of Beirut Medical Center, Riad El Solh, Beirut 1107 2020, Lebanon.
authors.forename: Samia J
authors.initials: SJ
authors.lastname: Khoury
authors.affiliation: Program in Translational NeuroPsychiatric Genomics, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Broad Institute at Harvard University and MIT, Boston, Massachusetts 02115, USA.
authors.forename: Wassim
authors.initials: W
authors.lastname: Elyaman
mesh_terms: D000818:Animals; D015551:Autoimmunity; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology / Q000473:pathology; D005260:Female; D006801:Humans; D020381:Interleukin-17 / Q000235:genetics / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3 / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D000075684:T-Lymphoma Invasion and Metastasis-inducing Protein 1 / Q000172:deficiency / Q000378:metabolism*; D058504:Th17 Cells / Q000378:metabolism; D014158:Transcription, Genetic; D020830:rac1 GTP-Binding Protein / Q000378:metabolism*
chemical_list: D020381:Interleukin-17; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; D000075684:T-Lymphoma Invasion and Metastasis-inducing Protein 1; D020830:rac1 GTP-Binding Protein