MEF2D sustains activation of effector Foxp3+ Tregs during transplant survival and anticancer immunity
Eros Di Giorgio, Liqing Wang, Yan Xiong, Tatiana Akimova, Lanette M. Christensen, Rongxiang Han, Arabinda Samanta, Matteo Trevisanut, Tricia R. Bhatti, Ulf H. Beier, Wayne W. Hancock
Eros Di Giorgio, Liqing Wang, Yan Xiong, Tatiana Akimova, Lanette M. Christensen, Rongxiang Han, Arabinda Samanta, Matteo Trevisanut, Tricia R. Bhatti, Ulf H. Beier, Wayne W. Hancock
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Research Article Immunology Oncology

MEF2D sustains activation of effector Foxp3+ Tregs during transplant survival and anticancer immunity

Abstract

The transcription factor MEF2D is important in the regulation of differentiation and adaptive responses in many cell types. We found that among T cells, MEF2D gained new functions in Foxp3+ T regulatory (Treg) cells due to its interactions with the transcription factor Foxp3 and its release from canonical partners, like histone/protein deacetylases. Though not necessary for the generation and maintenance of Tregs, MEF2D was required for the expression of IL-10, CTLA4, and Icos, and for the acquisition of an effector Treg phenotype. At these loci, MEF2D acted both synergistically and additively to Foxp3, and downstream of Blimp1. Mice with the conditional deletion in Tregs of the gene encoding MEF2D were unable to maintain long-term allograft survival despite costimulation blockade, had enhanced antitumor immunity in syngeneic models, but displayed only minor evidence of autoimmunity when maintained under normal conditions. The role played by MEF2D in sustaining effector Foxp3+ Treg functions without abrogating their basal actions suggests its suitability for drug discovery efforts in cancer therapy.

Authors

Eros Di Giorgio, Liqing Wang, Yan Xiong, Tatiana Akimova, Lanette M. Christensen, Rongxiang Han, Arabinda Samanta, Matteo Trevisanut, Tricia R. Bhatti, Ulf H. Beier, Wayne W. Hancock

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Figure 9

Mef2d deletion promotes anticancer immunity in mice bearing HCC.

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Mef2d deletion promotes anticancer immunity in mice bearing HCC. Shown ...
Shown is the analysis on day 9 after tumor cell injections, and additional data at 21 days after injection are shown in Supplemental Figure 11. (A) H&E-stained sections of WT and Mef2d–/– livers 9 days after the injection of 0.3 × 106 HCC cells into the mesenteric vein. Scale bar: 100 μm. Livers from WT show dense tumors, whereas livers from Mef2d–/– mice are tumor free. (B) Dot plot representing the AFP serum levels of 3 healthy C57BL/6 mice and 10 WT and 10 Mef2d–/– mice on day 9 after HCC injection; Tukey’s multiple-comparison test. (C–F) Analysis of the activation status of CD4+Foxp3– and CD8+ populations in terms of CD44hiCD62Llo (C), CD69 (D), and Ki67 positivity (F) and production of IFN-γ (E) in freshly isolated (C, D, and F) or PMA/ionomycin-stimulated (E) cells obtained from lymphoid tissues of HCC-injected mice. n = 5, t test. (G–I) Analysis of the expression of Ki67 (G), CTLA4 (H), and IL-10 (I) in CD4+Foxp3+ populations in freshly isolated (G) or PMA/ionomycin-stimulated (H and I) single-cell suspensions obtained from the same samples used for C. n = 5, t test. (J) qPCR results of the expression of the indicated genes in YFP+ Tregs obtained from the draining lymph nodes of WT and Mef2d–/– HCC-injected mice; n = 3–5, t test. (K) Immunoblots of Ki67, Crabp2, Fabp5, and CTLA4 in the same cells described in Figure 9J; β-actin served as loading control. *P < 0.05; **P < 0.01; ***P < 0.005.