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Mutations in 5-methylcytosine oxidase TET2 and RhoA cooperatively disrupt T cell homeostasis
Shengbing Zang, … , Deqiang Sun, Yun Huang
Shengbing Zang, … , Deqiang Sun, Yun Huang
Published July 10, 2017
Citation Information: J Clin Invest. 2017;127(8):2998-3012. https://doi.org/10.1172/JCI92026.
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Research Article Hematology Immunology Article has an altmetric score of 16

Mutations in 5-methylcytosine oxidase TET2 and RhoA cooperatively disrupt T cell homeostasis

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Abstract

Angioimmunoblastic T cell lymphoma (AITL) represents a distinct, aggressive form of peripheral T cell lymphoma with a dismal prognosis. Recent exome sequencing in patients with AITL has revealed the frequent coexistence of somatic mutations in the Rho GTPase RhoA (RhoAG17V) and loss-of-function mutations in the 5-methylcytosine oxidase TET2. Here, we have demonstrated that TET2 loss and RhoAG17V expression in mature murine T cells cooperatively cause abnormal CD4+ T cell proliferation and differentiation by perturbing FoxO1 gene expression, phosphorylation, and subcellular localization, an abnormality that is also detected in human primary AITL tumor samples. Reexpression of FoxO1 attenuated aberrant immune responses induced in mouse models adoptively transferred with T cells and bearing genetic lesions in both TET2 and RhoA. Our findings suggest a mutational cooperativity between epigenetic factors and GTPases in adult CD4+ T cells that may account for immunoinflammatory responses associated with AITL patients.

Authors

Shengbing Zang, Jia Li, Haiyan Yang, Hongxiang Zeng, Wei Han, Jixiang Zhang, Minjung Lee, Margie Moczygemba, Sevinj Isgandarova, Yaling Yang, Yubin Zhou, Anjana Rao, M. James You, Deqiang Sun, Yun Huang

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Figure 8

Tentative model depicting the dual modulation of FoxO1 through cooperative actions of TET2 and RhoA in murine CD4+ T cells.

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Tentative model depicting the dual modulation of FoxO1 through cooperati...
TET2-medaited 5mC oxidation is responsible for maintaining the proper methylation status of the FoxO1 promoter to regulate its transcription. RhoA GTPase signaling is required to balance the phosphorylation (P) state of Akt so as to control the phosphorylation of its downstream effector, FoxO1, which is indispensable for T cell proliferation and survival. Both pathways cooperatively work together to regulate the FoxO1-medaited signaling. Genetic defects in TET2 or RhoA alone may not exert an overtly detrimental effect on FoxO1. However, in patients with AITL or other types of PTCLs, TET2 loss of function and expression of the RhoA mutant (G17V) synergistically disrupt the transcriptional and posttranslational modification networks of CD4+ T cells, as most notably exemplified by combined FoxO1 inactivation through hypermethylation at its promoter region and elevated phosphorylation to drive the cytosolic translocation of nuclear FoxO1 to expedite its degradation. The inactivation of FoxO1 results in abnormal CD4+ T cell proliferation and survival and imbalanced T cell homeostasis to elicit an aberrant immune response and to further drive AITL disease progression.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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