title: Distinct inflammatory signals have physiologically divergent effects on epigenetic regulation of Foxp3 expression and Treg function.
abstract: Foxp3 expression in regulatory T cells (Treg) is required for their development and suppressive function. How different inflammatory signals affect Foxp3 chromatin structure, expression and Tregs plasticity are not completely known. In the present study, the Toll-like receptor 2 (TLR2) ligand peptidoglycan inhibited Foxp3 expression in both natural Treg (nTreg) and TGFβ-driven adaptive Treg (aTreg). Inhibition was independent of paracrine Th1, Th2 and Th17 cytokines. PGN-induced T cell-intrinsic TLR2-Myd88-dependent IFR1 expression and induced IRF1 bound to IRF1 response elements (IRF-E) in the Foxp3 promoter and intronic enhancers, and negatively regulated Foxp3 expression. Inflammatory IL-6 and TLR2 signals induced divergent chromatin changes at the Foxp3 locus and regulated Treg suppressor function, and in an islet transplant model resulted in differences in their ability to prolong graft survival. These findings are important for understanding how different inflammatory signals can affect the transplantation tolerance and immunity.
authors.affiliation: Department of Surgery and Microbiology and Immunology and the Center for Vascular and Inflammatory, University of Maryland, Baltimore, MD, USA. glal@nccs.res.in [corrected]
authors.forename: G
authors.initials: G
authors.lastname: Lal
authors.forename: N
authors.initials: N
authors.lastname: Yin
authors.forename: J
authors.initials: J
authors.lastname: Xu
authors.forename: M
authors.initials: M
authors.lastname: Lin
authors.forename: S
authors.initials: S
authors.lastname: Schroppel
authors.forename: Y
authors.initials: Y
authors.lastname: Ding
authors.forename: I
authors.initials: I
authors.lastname: Marie
authors.forename: D E
authors.initials: DE
authors.lastname: Levy
authors.forename: J S
authors.initials: JS
authors.lastname: Bromberg
mesh_terms: D000818:Animals; D044127:Epigenesis, Genetic; D005260:Female; D051858:Forkhead Transcription Factors / Q000235:genetics* / Q000276:immunology*; D018836:Inflammation Mediators / Q000502:physiology*; D050856:Interferon Regulatory Factor-1 / Q000172:deficiency / Q000235:genetics / Q000276:immunology; D015850:Interleukin-6 / Q000172:deficiency / Q000235:genetics / Q000276:immunology; D016381:Islets of Langerhans Transplantation / Q000276:immunology; D008024:Ligands; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D050791:STAT Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism; D051195:Toll-Like Receptor 2 / Q000172:deficiency / Q000235:genetics / Q000276:immunology; D016212:Transforming Growth Factor beta / Q000494:pharmacology
chemical_list: D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D018836:Inflammation Mediators; D050856:Interferon Regulatory Factor-1; D015850:Interleukin-6; C494258:Irf1 protein, mouse; D008024:Ligands; D050791:STAT Transcription Factors; C493486:Tlr2 protein, mouse; D051195:Toll-Like Receptor 2; D016212:Transforming Growth Factor beta