Regulatory T cells are crucial for the control of immune-mediated pathology during organ transplant rejection and autoimmune disease, therefore understanding the underlying mechanisms by which these cells function will be critical for promoting immune tolerance in humans. Recent studies in experimental models have established that Foxp3, which is a member of the forkhead family of DNA binding proteins, is necessary and sufficient for specification of regulatory T lymphocyte lineage choice and function. and therefore is crucial for acquired immune tolerance. Expression of Foxp3 initiates a unique transcriptional program which includes the induction of genes such as GITR, CD25, CTLA-4, IL-10 and TGF2, and repression of pro-inflammatory cytokine genes such as IL-2 and IFN?. The mechanisms by which Foxp3 enforces this genetic program are unclear. The studies proposed in this application are centered around basic questions of how Foxp3 binds to target genes, and how Foxp3 represses or induces transcription at these loci. The proposed studies will add significantly to our understanding of how Foxp3 regulates gene expression, and the information gained from these studies will have relevance for the design of novel therapeutic strategies by which tolerance can be promoted in humans.
|Johnson, Matthew E; Deliard, Sandra; Zhu, Fengchang et al. (2014) A ChIP-seq-defined genome-wide map of MEF2C binding reveals inflammatory pathways associated with its role in bone density determination. Calcif Tissue Int 94:396-402|
|Thomas, Rajan M; Gamper, Christopher J; Ladle, Brian H et al. (2012) De novo DNA methylation is required to restrict T helper lineage plasticity. J Biol Chem 287:22900-9|
|Thomas, Rajan M; Sai, Hong; Wells, Andrew D (2012) Conserved intergenic elements and DNA methylation cooperate to regulate transcription at the il17 locus. J Biol Chem 287:25049-59|
|Wells, Andrew D (2010) Mutiny on the Boun-T: controlling dangerous T cells through anergy. Discov Med 9:16-9|
|Thomas, Rajan M; Chen, Chunxia; Chunder, Neelanjana et al. (2010) Ikaros silences T-bet expression and interferon-gamma production during T helper 2 differentiation. J Biol Chem 285:2545-53|
|Torgerson, Troy R; Genin, Anna; Chen, Chunxia et al. (2009) FOXP3 inhibits activation-induced NFAT2 expression in T cells thereby limiting effector cytokine expression. J Immunol 183:907-15|