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Role of TCR signaling molecules in inflammatory diseases of the CNS

T cell receptor (TCR)-mediated signals play an important role in differentiation, activation and polarization of conventional T cells (Tconv) and regulatory T cells (Treg) and polymorphism or deficiency for TCR signaling genes could predispose to immune-mediated diseases. In this regards, our recent genetic studies have pointed out the TCR signaling gene Vav1 as a susceptibility factor for multiple sclerosis, myasthenia gravis and rheumatoid arthritis. Recently, we showed that Vav1/CD226 (DNAM-1) signaling pathway controls Th17 polarization and that the integrity of Vav1/Themis1 TCR signaling hub plays a crucial role in the suppressive activity of Treg. However, the cellular and molecular mechanisms by which these signaling molecules cooperate to regulate T cell function remain unknown.

The objectives of our project are therefore to:
AIM1: To demonstrate, using novel genetically engineered murine models, that Themis1 and Vav1 collaborate in order to prevent the emergence of autoimmune or inflammatory disorders through Treg cells.
AIM2: To analyze the impact of genetic variants of the CD226/Vav1 signaling on T cell functions.
AIM3: To decipher the molecular mechanisms by which the Themis1/Vav1 signaling hub and CD226 variants influence susceptibility to autoimmunity.

Selected publications

Kassem S, Gaud G, Bernard I, Benamar M, Dejean AS, Liblau R, Fournié GJ, Colacios C, Malissen B, Saoudi A.
A Natural Variant of the T Cell Receptor-Signaling Molecule Vav1 Reduces Both Effector T Cell Functions and Susceptibility to Neuroinflammation.
PLoS Genet. 2016 Jul 20.

Pedros C, Gaud G, Bernard I, Kassem S, Chabod M, Lagrange D, Andreoletti O, Dejean AS, Lesourne R, Fournié GJ, Saoudi A.
An epistatic interaction between Themis1 and Vav1 modulates regulatory T cell function and inflammatory bowel disease development
J Immunol. 2015 Aug 15;195(4):1608-16. doi: 10.4049/jimmunol.1402562.

Chabod M, Pedros C, Lamouroux L, Colacios C, Bernard I, Lagrange D, Balz-Hara D, Mosnier JF, Laboisse C, Vergnolle N, Andreoletti O, Roth MP, Liblau R, Fournié GJ, Saoudi A, Dejean AS.
A spontaneous mutation of the rat Themis gene leads to impaired function of regulatory T cells linked to inflammatory bowel disease.
PLoS Genet. 2012 Jan.

Colacios C, Casemayou A, Dejean AS, Gaits-Iacovoni F, Pedros C, Bernard I, Lagrange D, Deckert M, Lamouroux L, Jagodic M, Olsson T, Liblau RS, Fournié GJ, Saoudi A.
The p.Arg63Trp polymorphism controls Vav1 functions and Foxp3 regulatory T cell development.
J Exp Med. 2011 Oct 24.

Last updated November 10, 2016

Centre de physiopathologie de Toulouse Purpan - CHU Purpan - BP 3028 31024 Toulouse Cedex 3
Inserm University of Toulouse Université Toulouse III - Paul Sabatier