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

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

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 7

Reexpression of FoxO1 rescues the abnormalities of Tet2–/– RhoAG17V CD4+ T cells.

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Reexpression of FoxO1 rescues the abnormalities of Tet2–/– RhoAG17V CD4+...
(A) Experimental scheme of FoxO1 reexpression in WT or Tet2–/– RhoAG17V CD4+ T cells. GFP was used as a marker to monitor the expression of RhoAG17V or related controls, whereas mCherry signals indicated the expression of FoxO1-mCherry or mCherry as a control. GFP and mCherry double-positive cells were gated for further immunophenotypic analysis. (B and C) Representative flow cytometric plots of annexin V (B) and CellTrace (C) staining for in vitro–activated CD4+ T cells (WT, WT-FoxO1, Tet2–/– RhoAG17V, or Tet2–/– RhoAG17V–FoxO1). Bar graphs in B and C show statistical analyses of the flow cytometric data (n = 3 independent experiments). (D) In vitro–differentiated CD4+ T cells stained for the Treg marker Foxp3 and the Th17 marker IL-17α. WT or Tet2–/– naive T cells were transduced with retroviruses encoding mCherry or FoxO1-mCherry and then subjected to directed differentiation toward Tregs or Th17 cells. Bar graphs show immunostaining quantification (n = 3 independent experiments). Data represent the mean ± SD. *P < 0.05, **P < 0.01, and ***P < 0.001, by ANOVA with Tukey’s post-hoc correction.