Molecular antagonism and plasticity of regulatory and inflammatory T cell programs.

By Xuexian O. Yang, R. Nurieva, G. Martinez, H. Kang, Yeonseok Chung, B. Pappu, Bhavin Shah, S. Chang, K. Schluns, S. Watowich and 3 more. Immunity, 2008

1,222 citations recorded by the source corpus.

Regulatory T (Treg) and T helper 17 (Th17) cells were recently proposed to be reciprocally regulated during differentiation. To understand the underlying mechanisms, we utilized a Th17 reporter mouse with a red fluorescent protein (RFP) sequence inserted into the interleukin-17F (IL-17F) gene. Using IL-17F-RFP together with a Foxp3 reporter, we found that the development of Th17 and Foxp3(+) Treg cells was associated in immune responses. Although TGF-beta receptor I signaling was required for both Foxp3 and IL-17 induction, SMAD4 was only involved in Foxp3 upregulation. Foxp3 inhibited Th17 differentiation by antagonizing the function of the transcription factors RORgammat and ROR*. In contrast, IL-6 overcame this suppressive effect of Foxp3 and, together with IL-1, induced genetic reprogramming in Foxp3(+) Treg cells. STAT3 regulated Foxp3 downregulation, whereas STAT3, RORgamma, and ROR* were required for IL-17 expression in Treg cells. Our data demonstrate molecular antagonism and plasticity of Treg and Th17 cell programs.

Subfields: Immunology

View Paper: https://www.semanticscholar.org/paper/64073ad88a7979f9846b022eac78af399d8cd3b2

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In Immunology

1. W. E. Paul
2. Jinfang Zhu
3. V. Kuchroo
4. C. Dong
5. Shimon Sakaguchi
6. H. Yamane
7. M. Oukka
8. Yeonseok Chung

Citations in the corpus

• Th17 cells promote cytotoxic T cell activation in tumor immunity (2009, methodology): “IL-17A-deficient mice and IL-17F-RFP mice were generated in our lab (Yang et al., 2008).”
• IL-6 in inflammation, autoimmunity and cancer (2020, background): “IL-6 down-regulates Foxp3 expression through STAT3 and together with IL-1 induces the genetic reprogramming of T reg cells to express T h 17 cell function (191).”
• Differentiation of Effector CD4 T Cell Populations (2010, positive): “In parallel, STAT3 activation by IL-6 is responsible for Foxp3 downregulation in both differentiating and differentiated Tregs (24, 108, 112, 113), accounting for the critical role of IL-6 in determining the balance between Th17 and iTreg induction.”
• Development and maintenance of regulatory T cells. (2013, background): “For example, some Treg cells lose Foxp3 expression and differentiate into effector T cells (Komatsu et al., 2009; Xu et al., 2007; Yang et al., 2008; Zhou et al., 2009b).”
• TGF-β Activation and Function in Immunity (2013, background): “Mechanistically, Foxp3 and RORγt can directly interact with each other, and Foxp3 binding to RORγt inhibits RORγt function by preventing its interaction with the IL-17 gene promoter (104, 107, 108).”