Poster Presentation Lorne Infection and Immunity 2013

Modulation of T helper type 1-mediated autoimmunity via interactomic inhibition of T-bet (#141)

  1. Yonsei university, Seoul, South Korea

T-bet has been extensively studied during the last 25 years and understood in T helper cells, where it plays critical roles in regulating the development and maintenance of T helper type 1 cells. As a major regulator, T-bet induces the differentiation of Th1 cell subsets, which culminates in effective eradication of intracellular pathogens. On the other hand, T-bet can also be a decisive factor, when dysregulated, in causing pathogenic conditions induced by exuberant Th1 cell responses. Such pathogenic conditions are shown in patients with multiple sclerosis and rheumatoid arthritis. To find a therapeutic method for Th1-mediated inflammatory diseases, we constructed a cell-permeable form of T-box domain that the T-box family members including T-bet share. We found that tTbet-TMD(transducible Tbet-Transcriptional modulation domain) impairs the functional roles of endogenous wild-type T-bet by competitively inhibiting its DNA binding ability. Binding of tTbet-TMD proteins on promoter of Th1 marker genes such as IFNr, where wild-type T-bet should have been recruited to, prevents a complete formation of transcriptional complex for the activation of genes responsible for the optimal differentiation of Th1 cells. Expression of tTbet-TMD in Th1-polarizing conditions showed significantly lower expression of IFNr in an endogenous T-bet expressing environment. Here, we showed that intradermal injection of tTbet-TMD considerately alleviated the severity of arthritis in rheumatoid arthritis mouse models by reducing inflammatory cytokines. Thus, we expect tTbet-TMD to be a potent therapeutics for Th1-mediated autoimmune diseases.