Li, S.Floess, S.Hamann, A.Gaudieri, S.Lucas, A.Hellard, M.Roberts, S.Paukovic, G.Plebanski, M.Loveland, B.Aitken, C.Barry, S.Schofield, L.Gowans, E.John, W.E.2010-03-252010-03-252009PLoS Pathogens, 2009; 5(12):1000707-1-1000707-131553-73661553-7374http://hdl.handle.net/2440/57012We reported previously that a proportion of natural CD25+ cells isolated from the PBMC of HCV patients can further upregulate CD25 expression in response to HCV peptide stimulation in vitro, and proposed that virus-specific regulatory T cells (Treg) were primed and expanded during the disease. Here we describe epigenetic analysis of the FOXP3 locus in HCV-responsive natural CD25+ cells and show that these cells are not activated conventional T cells expressing FOXP3, but hard-wired Treg with a stable FOXP3 phenotype and function. Of ~46,000 genes analyzed in genome wide transcription profiling, about 1% were differentially expressed between HCV-responsive Treg, HCV-non-responsive natural CD25+ cells and conventional T cells. Expression profiles, including cell death, activation, proliferation and transcriptional regulation, suggest a survival advantage of HCV-responsive Treg over the other cell populations. Since no Treg-specific activation marker is known, we tested 97 NS3-derived peptides for their ability to elicit CD25 response (assuming it is a surrogate marker), accompanied by high resolution HLA typing of the patients. Some reactive peptides overlapped with previously described effector T cell epitopes. Our data offers new insights into HCV immune evasion and tolerance, and highlights the non-self specific nature of Treg during infection.en© 2009 Li et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.T-Lymphocyte SubsetsHumansHepatitis C, ChronicAntigens, ViralEpitopes, T-LymphocyteOligonucleotide Array Sequence AnalysisFlow CytometryCell SeparationGene Expression ProfilingReverse Transcriptase Polymerase Chain ReactionImmune ToleranceEpigenesis, GeneticT-Lymphocytes, RegulatoryForkhead Transcription FactorsInterleukin-2 Receptor alpha SubunitImmune EvasionJournal article002009477510.1371/journal.ppat.10007070002742270000302-s2.0-7454919929436169Barry, S. [0000-0002-0597-7609]Gowans, E. [0000-0002-4274-8311]