Date: Saturday, May 30, 2020
Session Time: 3:15pm-4:45pm
Presentation Time: 4:27pm-4:39pm
*Purpose: Foxp3+ T-regulatory (Treg) cells are crucial to immune homeostasis and self-tolerance, but the contributions to Tregs of the 4 large, multiprotein nuclear complexes (Sin3, NuRD, CoREST, MiDAC) that contain HDAC1/2, and typically repress gene expression in an evolutionarily conserved manner from yeast to humans, remain unknown.
*Methods: We evaluated one such prototypical transcriptional co-regulator, Sin3A, the central component of the Sin3A complex, for its role in Tregs by undertaking conditional deletion of floxed Sin3A in Cre-expressing Foxp3+ Treg cells.
*Results: Sin3A-/-Foxp3Cre mice developed severe, systemic autoimmunity, leading to death within 2-3 weeks of birth. These mice had greatly enlarged superficial lymph nodes, massive inflammatory lesions in lungs, skin, livers and kidneys and developed a range of autoantibodies to islet cells (ICA), striated muscles (anti-SM), keratin (AKA), endomysium (EMA) and gastric parietal cells (GPC). The proportions of CD4+ Foxp3+ Treg and the amount of Foxp3 protein per Tregs were significantly decreased (>3-fold) in all peripheral lymphoid organs, but especially in superficial lymph nodes, and Sin3A deficient Tregs produced significant amounts of pro-inflammatory cytokines, including Granzyme B, IFN-γ and IL-2 (ranging from 12-45% of cells), indicative of compromised Treg physiologic functions. In addition to its effects on thymic Tregs, Sin3A was essential for peripheral iTreg conversion since conventional CD4+CD25- cells from Sin3A-/-Foxp3Cre mice completely lacked the ability to convert to Foxp3+ iTregs ex vivo in the presence of IL-2 and TGFβ. Consistent with impaired Treg function, CD4+ and CD8+ T cells from Sin3A-/-Foxp3Cre mice showed increased activation ex vivo (Ki67+ and CD69+ increased by 120% and 230%, respectively) and enhanced production of inflammatory cytokines (Granzyme B, IFN-γ and IL-2) upon stimulation in vitro. Lastly, Tregs treated with a Sin3A pharmacologic inhibitor, Selamectin, which binds to the paired amphipathic helix (PAH2) domain of Sin3 and blocks its interaction with a variety of transcription factors, displayed a dose-dependent reduction of suppressive function, and wild-type CD4+CD25- cells treated with Selamectin also showed significantly reduced iTreg conversion.
*Conclusions: Our data show that rather than acting as a repressor of Foxp3 and Treg gene expression, or being redundant, given continuing expression of its close paralog (Sin3B), Sin3A unexpectedly appears to promote Treg gene expression and maintain the unique properties of these key immune cells. In addition, these data indicate a potential for therapeutic modulation of Foxp3+ Treg functions by pharmacologic targeting of components of the Sin3A complex.
To cite this abstract in AMA style:Christensen LM, Akimova T, Han R, Wang L, Samanta A, Hancock WW. Unexpected Regulation of Foxp3+ Treg Production, Stability and Function by the Nuclear Co-Repressor, Sin3A [abstract]. Am J Transplant. 2020; 20 (suppl 3). https://atcmeetingabstracts.com/abstract/unexpected-regulation-of-foxp3-treg-production-stability-and-function-by-the-nuclear-co-repressor-sin3a/. Accessed February 27, 2021.
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