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Transcriptional regulation of Th2 differentiation

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Naïve CD4 T cells have a series of fates open to them; differentiation to Th2 cells depends on the concerted action of three transcription factors, GATA-3, STAT5 and Gfi-1, and displays striking positive reinforcement. The earliest events in Th2 differentiation are T cell receptor driven induction of GATA-3 and of IL-2, the latter activating STAT5. GATA-3 and STAT-5, acting together, lead to early transcription of IL-4. Endogenous IL-4, acting through IL-4Rα and STAT6 strikingly upregulate GATA-3 and IL-4, leading to commitment of the cell to high rate IL-4 production and to the Th2 phenotype. GATA-3 and STAT5 target distinct sites within the Il4 gene, resulting in accessibility and thus the two transcription factors work in concert to activate the gene. Gfi-1 enhances the cytokine driven out-growth of Th2 cells and selects cells expressing the highest amounts of GATA-3. Thus, the interaction of the three transcription factors leads both to Th2 fate determination and selective outgrowth of differentiated Th2 cells and are thus responsible for a robust differentiation process resulting in the appearance of CD4 T cells capable of producing IL-4 and its related cytokines.

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Correspondence to William E Paul.

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Open Access This article is published under license to BioMed Central Ltd. This is an Open Access article is distributed under the terms of the Creative Commons Attribution 2.0 International License (https://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Keywords

  • STAT5 Target
  • Positive Reinforcement
  • Concerted Action
  • Selective Outgrowth
  • Distinct Site