15 déc.

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Transcription factors in normal and pathological immune responses

Our group main interest is to dissect the cellular and molecular mechanisms whereby transcription factors drive pathogenic CD4 T cell differentiation.

We recently demonstrated that the transcription factor Foxo3 plays a key role in the physiopathology of CNS autoimmunity since Foxo3-deficiency is associated with a significant decrease in the severity of EAE. We also provided evidence that this decreased severity of EAE is the consequence of the inability of Foxo3-deficient CD4 T cells to differentiate into pathogenic T helper-1 (Th1) cells producing interferon-(IFN-and granulocyte monocyte colony stimulating factor (GM-CSF).

At the molecular level, we identified Eomes as a direct target gene for Foxo3 in CD4+ T cells and we have shown that lentiviral-based overexpression of Eomes in Foxo3-deficient CD4+ T cells restored both IFN and GM-CSF production. Thus, the Foxo3-Eomes pathway is central to achieve the complete specialized gene program required for pathogenic Th1 cell differentiation and development of neuroinflammation.

In direct line with these data, our current project is to analyze the functions of the transcription factor Eomes in normal and pathological conditions and to evaluate the relevance of our results in humans by assessing the impact of a functional defect of FOXO3 and/or EOMES on T cell function from healthy donors or MS patients.

Some auto reactive T cells express TCR recognising several self-antigens. For instance in C57BL/6 mice, a third of MOG-specific CD4 T cells also recognise neurofilament medium. We investigate the dynamics of the bi-reactive T cell response: the timing and location of their priming, expansion and avidity-maturation, and their relative dominance during disease induction and chronicity. Furthermore, using adoptive transfer and specific tolerance induction strategies we will directly assess the pathogenicity of MOG mono vs. MOG / NF-M bi-specific T cells. Lastly, we will address how immune tolerance is imposed on T cells that co-recognize 2 unrelated neural self-antigens. These studies aim to better delineate how polyspecificity of T cells impacts on induction and regulation of an organ-specific autoimmune disease.

Selected publications

Stienne C, Michieletto MF, Benamar M, Carrié N, Bernard I, Nguyen XH, Lippi Y, Duguet F, Liblau RS, Hedrick SM, Saoudi A, Dejean AS.
Foxo3 Transcription Factor Drives Pathogenic T Helper 1 Differentiation by Inducing the Expression of Eomes.
Immunity. 2016 Oct 18.

Dejean AS, Beisner DR, Ch'en IL, Kerdiles YM, Babour A, Arden KC, Castrillon DH, DePinho RA, Hedrick SM.
Transcription factor Foxo3 controls the magnitude of T cell immune responses by modulating the function of dendritic cells.
Nat Immunol. 2009 May.


Last updated November 9, 2016

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