Inhibiting the coregulator CoREST impairs Foxp3+ Treg function and promotes antitumor immunity
Yan Xiong, Liqing Wang, Eros Di Giorgio, Tatiana Akimova, Ulf H. Beier, Rongxiang Han, Matteo Trevisanut, Jay H. Kalin, Philip A. Cole, Wayne W. Hancock
Yan Xiong, Liqing Wang, Eros Di Giorgio, Tatiana Akimova, Ulf H. Beier, Rongxiang Han, Matteo Trevisanut, Jay H. Kalin, Philip A. Cole, Wayne W. Hancock
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Research Article Immunology Oncology

Inhibiting the coregulator CoREST impairs Foxp3+ Treg function and promotes antitumor immunity

Abstract

Foxp3+ Tregs are key to immune homeostasis, but the contributions of various large, multiprotein complexes that regulate gene expression remain unexplored. We analyzed the role in Tregs of the evolutionarily conserved CoREST complex, consisting of a scaffolding protein, Rcor1 or Rcor2, plus Hdac1 or Hdac2 and Lsd1 enzymes. Rcor1, Rcor2, and Lsd1 were physically associated with Foxp3, and mice with conditional deletion of Rcor1 in Foxp3+ Tregs had decreased proportions of Tregs in peripheral lymphoid tissues and increased Treg expression of IL-2 and IFN-γ compared with what was found in WT cells. Mice with conditional deletion of the gene encoding Rcor1 in their Tregs had reduced suppression of homeostatic proliferation, inability to maintain long-term allograft survival despite costimulation blockade, and enhanced antitumor immunity in syngeneic models. Comparable findings were seen in WT mice treated with CoREST complex bivalent inhibitors, which also altered the phenotype of human Tregs and impaired their suppressive function. Our data point to the potential for therapeutic modulation of Treg functions by pharmacologic targeting of enzymatic components of the CoREST complex and contribute to an understanding of the biochemical and molecular mechanisms by which Foxp3 represses large gene sets and maintains the unique properties of this key immune cell.

Authors

Yan Xiong, Liqing Wang, Eros Di Giorgio, Tatiana Akimova, Ulf H. Beier, Rongxiang Han, Matteo Trevisanut, Jay H. Kalin, Philip A. Cole, Wayne W. Hancock

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Figure 1

Association of Foxp3 with the CoREST complex.

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Association of Foxp3 with the CoREST complex. (A) In HEK-293T cells tran...
(A) In HEK-293T cells transfected with tagged constructs encoding Foxp3 (47 kD), Rcor1 (44 kD), and Rcor2 (53 kD), IP of Foxp3 led to co-IP of Rcor1 but not Rcor2 protein. (B) In HEK-293T cells transfected with the same Foxp3, Rcor1, and Rcor2 constructs as shown in A, plus HA-tagged p300, IP of Rcor1 led to co-IP of Foxp3, Rcor2, and p300. (C) Lysates of Tregs isolated from lymph nodes and spleens of WT B6 mice were subjected to IP using anti-Rcor1 Ab or control IgG; Rcor1 and Rcor1-associated Foxp3 were detected by immunoblotting. (D) Tregs isolated from B6 lymph nodes and spleens after expansion in vivo (rIL-2/anti–IL-2, 3 days) were subjected to IP using anti-Foxp3 Ab or control IgG; shown is IB detection of Foxp3 and Foxp3-associated Rcor1. (E) Western blots of Rcor1 and Foxp3 expression in Tregs and Teff cells from WT mice or those with conditional deletion of Rcor1 in their Tregs; β-actin was used as a loading control. (F) IP of Lsd1 from WT Tregs led to co-IP of Foxp3, whereas IP of Lsd1 from Rcor1–/– Tregs led to only trace levels of Foxp3 co-IP.