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 2

Generation and characterization of mice with conditionally deleted Mef2d in Foxp3+ Treg cells.

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Generation and characterization of mice with conditionally deleted Mef2d...
(A) Immunoblots of MEF2Dα1 and -α2 and Hdac9 in freshly isolated Teffs and Tregs obtained from WT and Mef2d–/– mice, as indicated; β-actin served as loading control. (B and C) Analysis of CD4+Foxp3+ cells in lymphoid tissues from Mef2d–/– or WT mice (n = 3); the experiment was repeated 2 times with 3 mice/group with similar results. *P < 0.05, **P < 0.01 by t test. LN, lymph nodes; SP, spleen, THY, thymus. (D–G) Analysis of CD4+CD69+ and CD4+CD44hiCD62Llo cells in CD4+YFP– populations in lymphoid tissues from Mef2d–/– or WT mice (n = 3); the experiment was repeated 2 times with 3 mice/group with similar results. *P < 0.05, **P < 0.01 by t test. (H and I) In vitro Treg suppression assay using pooled (4 mice/group) Tregs from lymph nodes and spleens of Mef2d–/– or WT mice and WT T cells; the percentage of WT proliferating cells is shown in each panel. The experiment was run in triplicate and repeated at least 3 times, and the results of one representative experiment are shown. (J) AUC ratios (KO/WT, 1-sample t test with theoretical mean = 1) of 3 Treg suppression assays performed on CFSE-labeled WT splenocytes as responder cells. The suppressive effects on CD4+ and CD8+ responder cells were evaluated after CD4 and CD8 immunostaining.