title: An Epistatic Interaction between Themis1 and Vav1 Modulates Regulatory T Cell Function and Inflammatory Bowel Disease Development.
abstract: The development of inflammatory diseases depends on complex interactions between several genes and various environmental factors. Discovering new genetic risk factors and understanding the mechanisms whereby they influence disease development is of paramount importance. We previously reported that deficiency in Themis1, a new actor of TCR signaling, impairs regulatory T cell (Treg) function and predisposes Brown-Norway (BN) rats to spontaneous inflammatory bowel disease (IBD). In this study, we reveal that the epistasis between Themis1 and Vav1 controls the occurrence of these phenotypes. Indeed, by contrast with BN rats, Themis1 deficiency in Lewis rats neither impairs Treg suppressive functions nor induces pathological manifestations. By using congenic lines on the BN genomic background, we show that the impact of Themis1 deficiency on Treg suppressive functions depends on a 117-kb interval coding for a R63W polymorphism that impacts Vav1 expression and functions. Indeed, the introduction of a 117-kb interval containing the Lewis Vav1-R63 variant restores Treg function and protects Themis1-deficient BN rats from spontaneous IBD development. We further show that Themis1 binds more efficiently to the BN Vav1-W63 variant and is required to stabilize its recruitment to the transmembrane adaptor LAT and to fully promote the activation of Erk kinases. Together, these results highlight the importance of the signaling pathway involving epistasis between Themis1 and Vav1 in the control of Treg suppressive function and susceptibility to IBD development.
authors.affiliation: Unité Mixte de Recherche, INSERM, U1043, 31300 Toulouse, France; Unité Mixte de Recherche, Centre National de la Recherche Scientifique, U5282, 31300 Toulouse, France; Université de Toulouse, Université Paul Sabatier, Centre de Physiopathologie de Toulouse Purpan, 31300 Toulouse, France; and.
authors.forename: Christophe
authors.initials: C
authors.lastname: Pedros
authors.affiliation: Unité Mixte de Recherche, INSERM, U1043, 31300 Toulouse, France; Unité Mixte de Recherche, Centre National de la Recherche Scientifique, U5282, 31300 Toulouse, France; Université de Toulouse, Université Paul Sabatier, Centre de Physiopathologie de Toulouse Purpan, 31300 Toulouse, France; and.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Gaud
authors.affiliation: Unité Mixte de Recherche, INSERM, U1043, 31300 Toulouse, France; Unité Mixte de Recherche, Centre National de la Recherche Scientifique, U5282, 31300 Toulouse, France; Université de Toulouse, Université Paul Sabatier, Centre de Physiopathologie de Toulouse Purpan, 31300 Toulouse, France; and.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Bernard
authors.affiliation: Unité Mixte de Recherche, INSERM, U1043, 31300 Toulouse, France; Unité Mixte de Recherche, Centre National de la Recherche Scientifique, U5282, 31300 Toulouse, France; Université de Toulouse, Université Paul Sabatier, Centre de Physiopathologie de Toulouse Purpan, 31300 Toulouse, France; and.
authors.forename: Sahar
authors.initials: S
authors.lastname: Kassem
authors.affiliation: Unité Mixte de Recherche, INSERM, U1043, 31300 Toulouse, France; Unité Mixte de Recherche, Centre National de la Recherche Scientifique, U5282, 31300 Toulouse, France; Université de Toulouse, Université Paul Sabatier, Centre de Physiopathologie de Toulouse Purpan, 31300 Toulouse, France; and.
authors.forename: Marianne
authors.initials: M
authors.lastname: Chabod
authors.affiliation: Unité Mixte de Recherche, INSERM, U1043, 31300 Toulouse, France; Unité Mixte de Recherche, Centre National de la Recherche Scientifique, U5282, 31300 Toulouse, France; Université de Toulouse, Université Paul Sabatier, Centre de Physiopathologie de Toulouse Purpan, 31300 Toulouse, France; and.
authors.forename: Dominique
authors.initials: D
authors.lastname: Lagrange
authors.affiliation: Unité Mixte de Recherche, Institut National de la Recherche Agronomique, Ecole Nationale Vétérinaire de Toulouse 1225, Interactions Hôtes Agents Pathogènes, Ecole Nationale Vétérinaire de Toulouse, 31000 Toulouse, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Andréoletti
authors.affiliation: Unité Mixte de Recherche, INSERM, U1043, 31300 Toulouse, France; Unité Mixte de Recherche, Centre National de la Recherche Scientifique, U5282, 31300 Toulouse, France; Université de Toulouse, Université Paul Sabatier, Centre de Physiopathologie de Toulouse Purpan, 31300 Toulouse, France; and.
authors.forename: Anne S
authors.initials: AS
authors.lastname: Dejean
authors.affiliation: Unité Mixte de Recherche, INSERM, U1043, 31300 Toulouse, France; Unité Mixte de Recherche, Centre National de la Recherche Scientifique, U5282, 31300 Toulouse, France; Université de Toulouse, Université Paul Sabatier, Centre de Physiopathologie de Toulouse Purpan, 31300 Toulouse, France; and.
authors.forename: Renaud
authors.initials: R
authors.lastname: Lesourne
authors.affiliation: Unité Mixte de Recherche, INSERM, U1043, 31300 Toulouse, France; Unité Mixte de Recherche, Centre National de la Recherche Scientifique, U5282, 31300 Toulouse, France; Université de Toulouse, Université Paul Sabatier, Centre de Physiopathologie de Toulouse Purpan, 31300 Toulouse, France; and.
authors.forename: Gilbert J
authors.initials: GJ
authors.lastname: Fournié
authors.affiliation: Unité Mixte de Recherche, INSERM, U1043, 31300 Toulouse, France; Unité Mixte de Recherche, Centre National de la Recherche Scientifique, U5282, 31300 Toulouse, France; Université de Toulouse, Université Paul Sabatier, Centre de Physiopathologie de Toulouse Purpan, 31300 Toulouse, France; and abdelhadi.saoudi@inserm.fr.
authors.forename: Abdelhadi
authors.initials: A
authors.lastname: Saoudi
mesh_terms: D000818:Animals; D016207:Cytokines / Q000096:biosynthesis; D004195:Disease Models, Animal; D004843:Epistasis, Genetic; D005260:Female; D015212:Inflammatory Bowel Diseases / Q000235:genetics* / Q000276:immunology* / Q000473:pathology; D007413:Intestinal Mucosa / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D008297:Male; D009154:Mutation; D051567:Proto-Oncogene Proteins c-vav / Q000235:genetics* / Q000378:metabolism; D051381:Rats; D055647:Rats, Transgenic; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D015398:Signal Transduction; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism*; D060168:Thymocytes / Q000276:immunology / Q000378:metabolism
chemical_list: D016207:Cytokines; D047908:Intracellular Signaling Peptides and Proteins; D051567:Proto-Oncogene Proteins c-vav; D011948:Receptors, Antigen, T-Cell; C000602657:Themis1 protein, rat; C496620:Vav1 protein, rat