T cell factor 1 initiates the T helper type 2 fate by inducing the transcription factor GATA-3 and repressing interferon-γ

Qing Yu, et al. Nature Immunoogyl. 10(9):992-9 (2009)

Speaker：Wan-Chen Chung (鍾宛臻)              Time：13:00~14:00, Dec. 9, 2009

Commentator：Dr. Chiou-Feng Lin (林秋烽博士)   Place：Room 601

Abstract:

In response to specific cytokines, activated naive CD4⁺ T cells differentiate into helper T cell subsets, T helper type 1 (T_H1), T helper type 2 (T_H2) and T_H17 cells, in order to mediate immune responses. Once naive CD4⁺ T cells differentiate into T_H2 cells, they produce IL-4 and reinforce the T_H2 type response. It had been reported that in the absence of exogenous IL-4, T_H2 differentiation still occurs, suggesting that IL-4 produced by antigen-activated naive CD4⁺ T cells is sufficient to initiate T_H2 differentiation. IL-4 expression is regulated by the transcription factor GATA-3. There are many factors which regulate GATA-3 expression during T_H2 differentiation. T cell factor 1 (TCF-1) and β-catenin have been demonstrated to act together to play a key role of T cell development. The authors hence investigated the role of TCF-1and β-catenin in regulating GATA-3 expression. First the authors demonstrated that TCR-activated CD4⁺ T cells express GATA-3 mainly through GATA3-1b promoter in a STAT6- and IL-4-independent way. Next they used a specific inhibitor for the interaction between TCF-1 and β-catenin (ICAT), T cells from β-catenin-transgenic mice (β-CAT-Tg) and retrovirus express human CD8 and mtTCF-1 (MSCV-mtTCF-1) to demonstrate that TCF-1 acts with β-catenin to induce GATA-3 expression, which process is independent of IL-4, IL-4R and STAT6. The author went on to show that TCF-1 negatively regulates IFN-γ and thereby blocks T_H1 differentiation in a β-catenin independent manner. The authors then used a mouse model of allergic asthma to prove the role of TCF-1 in T_H2 differentiation. TCF-1-deficient mice has less T_H2 cytokine of IL-4 and weaker inflammation of lung, indicating the crucial role of TCF-1 in T_H2 immune response. This study indicates that TCF-1 initiates the T_H2 differentiation of activated CD4⁺ T cells by a dual mechanism of activation of GATA-3 and repression of IFN-γ.

References:

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