Key Event Title
|Level of Biological Organization|
Key Event Components
Key Event Overview
AOPs Including This Key Event
|AOP Name||Role of event in AOP|
|Exacerbation of SLE by activation of estrogen receptor||KeyEvent|
Key Event Description
Transcription factors are critical for Th cell differentiation and cytokine production. Cell fate determination in each lineage requires at least two types of transcription factors: the master regulators as well as the signal transducers and activator of transcription (STAT) proteins (Zhu J. 2010). The ability of STAT6: ER to induce a Th2 phenotype correlates with the induction of GATA-3 mRNA expression. GATA3 is the Th2 master regulator (Zhu J．2010, Sung-Yun. 2004, Zhu J. 2004, Zheng W. 1997, Zhang DH. 1997), but it also plays important roles in multiple steps of CD4 T cell development (Ho IC. 2009).
How It Is Measured or Detected
Purified naive T cells were cultured and expanded under Th1 culture conditions in the presence or absence of 0.3 μM 4-HT (Research Biochemicals Institute) for 2 weeks starting from days 1, 7, 14, or 21. GATA-3 mRNAs can be measured using RNase protection assay in developing Th1 cells. RNase protection assay was performed with RiboQuant multiprobe kit (PharMingen) following the manufacturer’s method using GATA-3. Stat6:ER Th1 cells expressed significant amounts of both GATA-3 mRNAs in a 4-HT-dependent manner. (Kurata H. 1999, Zhu J. 2001).
Constitutively activated Stat6 (Stat6VT) is primed under null Th cell (ThN) conditions in the absence of human (h)IL-4. The expression level of Gata3 in this primed cells are checked by RT-PCR (Zhu J. 2001).
Domain of Applicability
Involvement of GATA3 and STAT6 in Th2 cell development through ER is common in humans, rodents, and other mammalian species (Ho IC. 2009). A constitutively activated form of Stat6 introduced into CD4 T cells resulted in both Th2 differentiation and enhanced cell expansion. Stat6 is not only necessary but also sufficient to drive IL-4-mediated Th2 differentiation and cell expansion in naive CD4 T cells (Zhu J. 2001). CD4 T cells from Stat6-knockout mice are not able to drive Th2 differentiation and cell expansion under ThN conditions with added with IL-4 (Zhu J. 2001).
- Zhu J, Yamane H, Paul WE. Differentiation of effector CD4 T cell populations. Annu Rev Immunol. 2010; 28:445-89.
- Zhu J, Paul WE. Peripheral CD4 T cell differentiation regulated by networks of cytokines and transcription factors. Immunol Rev. 2010; 238(1):247-62.
- Sung-Yun, Morgan L. T. I-Cheng H. (2004). GATA-3 deficiency abrogates the development and maintenance of T helper type 2 cells. Proceedings of the National Academy of Sciences. 101 (7): 1993-1998.
- Zhu J, Min B, Paul WE, et al. Conditional deletion of Gata3 shows its essential function in T(H)1-T(H)2 responses. Nat Immunol. 2004;5(11):1157-65.
- Zheng W, Flavell RA. The transcription factor GATA-3 is necessary and sufficient for Th2 cytokine gene expression in CD4 T cells. Cell. 1997. 16;89(4):587-96.
- Zhang DH, Cohn L, Ray P, Bottomly K, Ray A. Transcription factor GATA-3 is differentially expressed in murine Th1 and Th2 cells and controls Th2-specific expression of the interleukin-5 gene. J Biol Chem. 1997. 22;272(34):21597-603.
- Zhu, J., Guo, L., Watson, C. J., Hu-Li, J. and Paul, W. E. (2001). STAT6 is necessary and sufficient for IL-4's role in Th2 differentiation and cellexpansion. The Journal of Immunology 166 (12): 7276-7281.
- Ho IC, Tai TS, Pai SY. GATA3 and the T-cell lineage: essential functions before and after Thelper-2-cell differentiation. Nat Rev Immunol. 2009;9(2):125-35.
- Kurata, H., Lee, H. J., O’Garra, A. and Arai, N. (1999). Ectopic expression of activated STAT6 induces the expression of Th2-specific cytokines and transcription factors in developing Th1 cells. Immunity 11: 677-688.