STAT3 Regulates Cytokine-mediated Generation of Inflammatory Helper T Cells*

By Xuexian O. Yang, Athanasia D. Panopoulos, R. Nurieva, S. Chang, Demin Wang, S. Watowich, C. Dong. Journal of Biological Chemistry, 2007

1,520 citations recorded by the source corpus.

Interleukin-17 (IL-17)-producing helper T (TH) cells, named as THIL-17, TH17, or inflammatory TH (THi), have been recently identified as a novel effector lineage. However, how cytokine signals mediate THi differentiation is unclear. We found that IL-6 functioned to up-regulate IL-23R and that IL-23 synergized with IL-6 in promoting THi generation. STAT3, activated by both IL-6 and IL-23, plays a critical role in THi development. A hyperactive form of STAT3 promoted THi development, whereas this differentiation process was greatly impaired in STAT3-deficient T cells. Moreover, STAT3 regulated the expression of retinoic acid receptor-related orphan receptor γ-T (RORγt), a THi-specific transcriptional regulator; STAT3 deficiency impaired RORγt expression and led to elevated expression of T-box expressed in T cells (T-bet) and Forkhead box P3 (Foxp3). Our data thus demonstrate a pathway whereby cytokines regulate THi differentiation through a selective STAT transcription factor that functions to regulate lineage-specific gene expression.

Subfields: Immunology

View Paper: https://www.semanticscholar.org/paper/a8b86a71b83838e9b22155a966ce479af8e920a2

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In Immunology

1. A. Jetten
2. C. Dong
3. Jinfang Zhu
4. Dan R. Littman
5. R. Flavell
6. D. Cua
7. Ming O. Li
8. J. O’Shea

Citations in the corpus

• TH17 cells in development: an updated view of their molecular identity and genetic programming (2008, background): “IL-6 was reported to be necessary for antigen-specific T H 17-cell differentiatio”
• Control of T(H)17/T(reg) balance by hypoxia-inducible factor 1. (2011, positive): “Though it is now known that Stat3 induces RORgt gene expression (Harris et al., 2007; Yang et al., 2007)—the key transcription factor required for TH17 development (Ivanov et al.”
• Plasticity of CD4+ T cell lineage differentiation. (2009, background): “Forced expression of an active form of Stat3 enhanced IL-17 expression in the presence of TGF-b, presumably by upregulation of RORgt expression and suppression of Foxp3 expression (Zhou et al., 2007; Yang et al., 2007).”
• IL-6 programs TH-17 cell differentiation by promoting sequential engagement of the IL-21 and IL-23 pathways (2007, background): “The IL-23 receptor (IL-23R), which forms dimers with the IL-12Rβ1 subunit shared by both IL-12 and IL-23, is expressed in lamina propria T cells only if IL-6 is present, and IL-23R mRNA is induced after treatment of activated T cells with IL-6 (ref”
• Generation of follicular helper T cells is mediated by IL-21 but independent of TH1, TH2 or TH17 lineages (2008, background): “Whereas IL-6 is necessary for 138 Immunity 29, 138–149, July 18, 2008 ª2008 Elsevier Inc. Th17 cell differentiation (Korn et al., 2007; Yang et al., 2007), IL-21 was recently reported as an autocrine factor induced by IL-6 to regulate Th17 cell differentiation (Korn et al., 2007; Nurieva et al.,…”