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 2

TET2 loss and RhoAG17V expression cause abnormal expansion of CD4+ T cells.

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TET2 loss and RhoAG17V expression cause abnormal expansion of CD4+ T cel...
(A) Peripheral blood analysis of GFP+ Thy1.1+ and Thy1.2+ T cell populations in recipient mice 8 weeks after transfer. Bar graph shows the ratio of GFP gated Thy1.2+ and Thy1.1+ T cells before (week 0) and 8 weeks after adoptive T cell transfer (n = 4 mice; 2 independent experiments). (B) Ki-67 staining of Thy1.2+ T cells in the peripheral blood of recipient mice 8 weeks after adoptive cell transfer. Bar graph shows the statistical analysis of Ki-67+ Thy1.2+ cells in each group (n = 3 mice; 3 independent experiments). (C) Peripheral blood analysis of Thy1.2 and GFP double-positive CD4+ and CD8+ T cells in the peripheral blood of recipient mice 8 weeks after adoptive transfer. (D) Statistical analysis of peripheral blood (PB) Thy1.2 and GFP double-positive CD4+/CD8+ T cell ratio at the indicated time points after T cell transfer (n = 3 mice; 3 independent experiments). (E) Representative FACS plots and (F) quantification of the ratio of CD4+/CD8+ T cells (gated by Thy1.2+GFP+) in peripheral lymphoid tissues (spleens and lymph nodes) derived from the indicated recipient mice (n = 3 mice; 3 independent experiments). (G) Representative flow cytometric profiles of Ki-67 staining of peripheral Thy1.2+CD4+ T cells isolated from recipient mice transferred with WT, RhoAG17V, Tet2–/–, or Tet2–/– RhoAG17V T cells 20 weeks after adoptive transfer (n = 3 mice, 3 independent experiments). Bar graph shows statistical analysis of the percentage of Ki-67+ cells. (H) Kaplan-Meier survival curves of recipient mice transferred with CD4+ or CD8+ T cells (WT vs. Tet2–/– RhoAG17V; n = 4 mice; 1 experiment). Data represent the mean ± SD. *P < 0.05 and **P < 0.01, by 2-tailed Student’s t test (A, D, and G) and ANOVA with Dunnett’s post-hoc correction (B and F).