*Purpose: While Foxp3+ T-regulatory (Treg) cells are well established as central players in regulation of allograft acceptance and tolerance, the contributions of several types of large multiprotein complexes that are thought to regulate gene expression via epigenetic mechanisms in essentially all cells remain unexplored in the case of Tregs. To this end, we have begun to analyze the role in Tregs of the evolutionarily highly conserved CoREST complex that consists of the scaffolding proteins Rcor1 and Rcor2, plus Hdac1 and/or Hdac2, and the H3K4me2 demethylase, Lsd1 (Kdm1a).

*Methods: We undertook biochemical, cellular and in vivo studies using WT or C57BL/6 mice with conditional deletion of RCOR1 in their Tregs as a result of mating floxed RCOR1 and Foxp3cre mice.

*Results: Pull-down of Rcor1 or Rcor2 each led to co-immunoprecipitation of Foxp3, as did pull-down of Lsd1 in WT but not Rcor1-deficient Treg cells, and Rcor1 was physically associated with p300, which is important for Foxp3 acetylation, dimerization and Treg function. Mice with conditional deletion of Rcor1 in Foxp3+ Treg cells developed normally and had normal proportions of Tregs in their lymph nodes, spleen and thymus. Expression of key Treg genes (e.g. Foxp3) was largely unaltered, except for that of IL-2, which is significantly increased in Rcor1-/- Treg vs. WT cells (p<0.001), and Rcor1-/- Tregs showed impaired Treg function in vitro compared to WT control cells. Moreover, whereas peritransplant CD154 mAb/donor specific transfusion (DST, 5x106 cells) induced permanent survival of BALB/c cardiac allografts in WT B6 recipients, mice with conditional deletion of Rcor1 in their Tregs were unable to maintain long-term allograft survival despite CD154/DST therapy (p<0.01). Conditionally deleted mice also showed enhanced antitumor immunity in syngeneic models.

*Conclusions: These studies indicate that the CoREST complex is intimately involved in regulation of Treg biology, including suppression of IL-2 production and maintenance of Treg suppressive function. While further investigation of the downstream targets of Foxp3 and the CoREST complex are required, our data point to the potential for modulation of Treg functions by pharmacologic targeting of enzymatic components of the complex, including Hdac1/2 and Lsd1. Such studies will contribute to an understanding of the biochemical and molecular mechanisms by which Foxp3 represses large gene sets and maintains the unique properties of this cell type.

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