MEF2D sustains activation of effector Foxp3+ Tregs during transplant survival and anticancer immunity
Eros Di Giorgio, … , Ulf H. Beier, Wayne W. Hancock
Eros Di Giorgio, … , Ulf H. Beier, Wayne W. Hancock
Published August 13, 2020
Citation Information: J Clin Invest. 2020;130(12):6242-6260. https://doi.org/10.1172/JCI135486.
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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 6

Mef2d deletion dampens Tfr functions partially affecting the Tfh-mediated regulation of B cell maturation.

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Mef2d deletion dampens Tfr functions partially affecting the Tfh-mediat...
(A and B) Analysis of Tfr (CD4+CXCR5+PD-1+Foxp3+) and Tfh (CD4+CXCR5+PD-1+Foxp3–) populations in lymphoid tissues from Mef2d–/– or WT mice. n = 5. **P < 0.01 by t test between WT and KO samples. (C) Analysis of B cell (CD19+), memory B cell (CD19+B220+CD62lo/–FAS–GL7–CD138–), and plasma cell (CD138+IgM–) populations in lymphoid tissues from Mef2d–/– or WT mice. n = 5; t test between WT and KO samples. (D–I) Analysis of B cell subpopulations in lymphoid tissues from Mef2d–/– or WT mice. (D) B1 cells (B220–CD19+); (E) follicular B cells (CD19+B220+CD93–CD21loCD23hi), follicular B type I cells (CD19+B220+CD93–CD21loCD23hiIgMlo), follicular B type II cells CD19+B220+CD93–CD21loCD23hiIgMhi); (F) marginal zone (MZ) precursor B cells (CD19+B220+CD93–CD21hiCD23lo) and MZ B cells (CD19+B220+CD93–CD21hiCD23hi); (H) transitional type 1 (T1) B cells (CD19+B220+CD93+IgM++CD23–), T2 B cells (CD19+B220+CD93+IgM++CD23+), and T3 B cells (CD19+B220+CD93+IgM–CD23+); (I) GC B cells (CD19+B220+GL7+FAS+) and GL7+ activated B cells (CD19+B220+GL7+). n = 5. *P < 0.05, **P < 0.01, ***P < 0.001 by t test between WT and KO samples. (J) Autoantibodies detected in the sera of 3 WT and 3 Mef2d–/– mice, using indirect immunofluorescence.