Stat6 Is Necessary and Sufficient for IL-4’s Role in Th2 Differentiation and Cell Expansion
Open accessAbstract
IL-4 plays a critical role in the differentiation of TCR-stimulated naive CD4 T cells to the Th2 phenotype. In response to IL-4, the IL-4R activates a set of phosphotyrosine binding domain-containing proteins, including insulin receptor substrate 1/2, Shc, and IL-4R interacting protein, as well as Stat6. Stat6 has been shown to be required for Th2 differentiation. To determine the roles of the phosphotyrosine binding adaptors in Th2 differentiation, we prepared a retrovirus containing a mutant of the human (h)IL-4R α-chain, Y497F, which is unable to recruit these adaptors. The mutant hIL-4Rα, as well as the wild-type (WT) hIL-4Rα, was introduced into naive CD4 T cells. Upon hIL-4 stimulation, Y497F worked as well as the WT hIL-4Rα in driving Th2 differentiation, as measured by Gata3 up-regulation and IL-4 production. Furthermore, IL-4-driven cell expansion was also normal in the cells infected with Y497F, although cells infected with Y497F were not capable of phosphorylating insulin receptor substrate 2. These results suggest that the signal pathway mediated by Y497 is dispensable for both IL-4-driven Th2 differentiation and cell expansion. Both WT and Y497F hIL-4Rα lose the ability to drive Th2 differentiation and cell expansion in Stat6-knockout CD4 T cells. A constitutively activated form of Stat6 introduced into CD4 T cells resulted in both Th2 differentiation and enhanced cell expansion. Thus, activated Stat6 is necessary and sufficient to mediate both IL-4-driven Th2 differentiation and cell expansion in CD4 T cells.
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IL-4 dependent STAT6 phosphorylation plays a critical role during Th2 differentiation.
“IL-4 dependent STAT6 phosphorylation has been reported to play a critical role during Th2 differentiation [31].”
The STAT6 signaling pathway is mainly induced by IL-4, which induces the expression of GATA3.
“The STAT6 signaling pathway is mainly induced by IL-4, which induces the expression of GATA3 [31, 40].”
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Cites
Zheng, W.-P., & Flavell, R. A. (1997) · Cell · doi:10.1016/s0092-8674(00)80240-8 · Cited by 2,384 · see citing works
The IL-4 receptor: signaling mechanisms and biologic functions
Nelms, K., Keegan, A. D., Zamorano, J., Ryan, J. J., & Paul, W. E. (1999) · Annual Review of Immunology · doi:10.1146/annurev.immunol.17.1.701 · Cited by 1,545 · cited 2× · see citing works
“Stat6 interacts with the second, third, and fourth conserved tyrosines (Y575, Y603, and Y631) of IL-4Ra (2, 17, 18).”
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- Wang, L. M., A. D. Keegan, W. Li, G. E. Lienhard, S. Pacini, J. S. Gutkind, M. G. Myers, Jr, X. J. Sun, M. F. White, S. A. Aaronson, et al. 1993. Common elements in interleukin 4 and insulin signaling pathways in factor-dependent he- matopoietic cells. Proc. Natl. Acad. Sci. USA 90:4032.
- Pernis, A., B. Witthuhn, A. D. Keegan, K. Nelms, E. Garfein, J. N. Ihle, W. E. Paul, J. H. Pierce, and P. Rothman. 1995. Interleukin 4 signals through two related pathways. Proc. Natl. Acad. Sci. USA 92:7971.
- Dent, A. L., J. Hu-Li, W. E. Paul, and L. M. Staudt. 1998. T helper type 2 inflammatory disease in the absence of interleukin 4 and transcription factor STAT6. Proc. Natl. Acad. Sci. USA 95:13823.
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Zhu, J., Yamane, H., & Paul, W. E. (2010) · Annual Review of Immunology · doi:10.1146/annurev-immunol-030409-101212 · Cited by 3,452 · see citing works
Self-citationCD4 <sup>+</sup> T Cells: Differentiation and Functions
Luckheeram, R. V., Zhou, R., Verma, A. D., & Xia, B. (2012) · Clinical and Developmental Immunology · doi:10.1155/2012/925135 · Cited by 1,381 · see citing works
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Cai, W., Dai, X., Chen, J., Zhao, J., Xu, M., Zhang, L., Yang, B., Zhang, W., Rocha, M., Nakao, T., et al. (2019) · JCI Insight · doi:10.1172/jci.insight.131355 · Cited by 317 · see citing works
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O'Shea, J. J., Lahesmaa, R., Vahedi, G., Laurence, A., & Kanno, Y. (2011) · Nature Reviews Immunology · doi:10.1038/nri2958 · Cited by 295 · see citing works
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Mowen, K. A., & Glimcher, L. H. (2004) · Immunological Reviews · doi:10.1111/j.0105-2896.2004.00209.x · Cited by 255 · see citing works
T-helper cell type-2 regulation in allergic disease
Georas, S. N., Guo, J., De Fanis, U., & Casolaro, V. (2005) · European Respiratory Journal · doi:10.1183/09031936.05.00006005 · Cited by 181 · see citing works
Choi, J., Choi, B. K., Kim, J. S., Lee, J.-W., Park, H. A., Ryu, H. W., Lee, S. U., Hwang, K. W., Yun, W.-K., Kim, H.-C., et al. (2016) · PLOS ONE · doi:10.1371/journal.pone.0167098 · Cited by 30 · see citing works
- Authors
- Zhu, J., Guo, L., Watson, C. J., Hu-Li, J., & Paul, W. E.
- Affiliations
- National Institutes of Health (US)
- Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health , Bethesda, MD 20892
- Venue
- The Journal of Immunology
- Publisher
- Oxford University Press (OUP)
- Published
- 2001-06
- Volume
- 166
- Issue
- 12
- Pages
- 7276-7281
- ISSN
- 0022-1767 (ISSN-L)
- 1550-6606
- OpenAlex
- W1602470456
- Cited by
- 301
- References
- 2
- Citations by year
- 2026: 5 · 2025: 11 · 2024: 7 · 2023: 9 · 2022: 12 · 2021: 15 · 2020: 13 · 2019: 12 · 2018: 10 · 2017: 14 · 2016: 10 · 2015: 12 · 2014: 17 · 2013: 14 · 2012: 20
- FWCI
- 5.61
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The Journal of Immunology (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Life Sciences › Immunology and Microbiology › Immunology › Psoriasis: Treatment and Pathogenesis
- Keywords
- STAT6, IL-4, Th2 differentiation, CD4+ T cells, IL-4 receptor alpha, insulin receptor substrate 2, GATA3, T cell expansion, retroviral gene transfer
- MeSH terms
- Animals, Cell Differentiation, Cells, Cultured, Genetic Vectors, Immune Sera, Lymphocyte Activation, Mice, Inbred BALB C, Phosphoproteins, Phosphorylation, Tyrosine, Signal Transduction, CD4-Positive T-Lymphocytes, Trans-Activators, Interleukin-4, Mutagenesis, Site-Directed, CD3 Complex, Mice, Knockout, Th2 Cells, Coculture Techniques, Intracellular Signaling Peptides and Proteins, STAT6 Transcription Factor, Mice, Insulin Receptor Substrate Proteins
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