Abstract A190: Mechanisms governing Foxp3-dependent and -independent gene expression in regulatory T-cells in evolutionary distant mice

Abstract

Abstract T regulatory (Treg) cells expressing the forkhead box transcription factor (Foxp3) are important regulators of immunity and play a key role in cancer and metastasis by controlling the activity of effector T-cells. Lineage-specifying transcription factors (TFs) establish cell identity and maintain cell specific transcriptional programs. Foxp3 is a key master TF controlling various Treg cell developmental and functional modalities. Foxp3 deficiency in humans and mice causes a life threatening autoimmune disease, and the enforced expression of Foxp3 in CD4+ T-cells confers suppressor functions. However, our understanding of Treg cell regulation during differentiation in the thymus, and in mature Treg cells in the periphery, whether Foxp3 dependent or independent, is still lacking. Single-nucleotide polymorphism (SNPs) may occur within coding genes or noncoding genomic regulatory areas and can have severe phenotypic consequences. We have recently attempted to link SNPs with differential Treg transcriptomic and epigenetic features in humans. However, such studies are limited by their intrinsic correlative nature, and by the limited number of SNPs. Here we use evolutionally distant mice strains C57Bl/6 (B6), CAST/EiJ (Cast) and SPRET/EiJ (Spret), to identify allele-specific imbalances and functional differences in the transcriptional and epigenetic programs during differentiation and in various conditions of Treg cells and their precursors. Using Foxp3 reporter and conditional knockout (KO) systems combined with interbreeding of the evolutionary distant mice strains in vivo, we explore the genetic and molecular mechanisms of Treg cell differentiation and function, employing high-throughput genomic methods including RNA-seq, ATAC-seq and Chip-seq. Such studies may pave a way for the development of novel therapeutic approaches to treat cancer and metastasis. Citation Format: Ariella Glasner, Yi Zhong, Joris Van Der Veeken, Alexander Rudensky. Mechanisms governing Foxp3-dependent and -independent gene expression in regulatory T-cells in evolutionary distant mice [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr A190.