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 1

Recipient mice transferred with Tet2–/– RhoAG17V T cells have an inflammatory phenotype.

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Recipient mice transferred with Tet2–/– RhoAG17V T cells have an inflamm...
(A) Schematic representation of the experimental design for competitive adoptive T cell transfer experiments. Thy1.2+ T cells transduced with the corresponding retroviruses were mixed at a 1:1 ratio with control Thy1.1+ T cells and transferred into TCRα-deficient (Tcra–/–) recipient mice by retro-orbital injection to characterize the functional consequences following Tet2 deletion (Tet2–/–) and/or RhoAG17V expression. (B) Kaplan-Meier survival curves for recipient mice transferred with Thy1.2+ WT (black), RhoAG17V (blue), Tet2–/– (green), or Tet2–/– RhoAG17V (red) T cells (n = 10 mice per group; 3 independent experiments). Only the mice transferred with Tet2–/– RhoAG17V T cells showed lethal activity, with a median survival of 21.3 weeks. (C) Weight measurement of the surviving recipient mice 20 weeks after T cell transfer (n = 7 mice; 2 independent experiments). ***P < 0.001, by ANOVA with Dunnett’s post-hoc correction. (D) Representative images of lymph nodes from recipient Tcra–/– mice 20 weeks after adoptive transfer of WT, RhoAG17V, Tet2–/–, or Tet2–/RhoAG17V T cells. (E) H&E staining of heart, lung, and skin tissues and lymph nodes isolated from recipient mice transferred with WT, RhoAG17V, Tet2–/–, or Tet2–/– RhoAG17V T cells (20 weeks after adoptive transfer). Scale bar: 100 μm. Original magnification: ×4. (F) Immunohistochemical staining for anti-CD3 (T cell marker) and anti-B220 (B cell maker) in lung tissues isolated from 20-week-old recipient mice transferred with WT or Tet2–/– RhoAG17V T cells. Scale bar: 100 μm.