title: Analysis of FOXP3+ regulatory T cells that display apparent viral antigen specificity during chronic hepatitis C virus infection.
abstract: We 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 approximately 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.
authors.affiliation: Macfarlane Burnet Institute for Medical Research and Public Health, Melbourne, Victoria, Australia. shuo.li@burnet.edu.au
authors.forename: Shuo
authors.initials: S
authors.lastname: Li
authors.forename: Stefan
authors.initials: S
authors.lastname: Floess
authors.forename: Alf
authors.initials: A
authors.lastname: Hamann
authors.forename: Silvana
authors.initials: S
authors.lastname: Gaudieri
authors.forename: Andrew
authors.initials: A
authors.lastname: Lucas
authors.forename: Margaret
authors.initials: M
authors.lastname: Hellard
authors.forename: Stuart
authors.initials: S
authors.lastname: Roberts
authors.forename: Geza
authors.initials: G
authors.lastname: Paukovic
authors.forename: Magdalena
authors.initials: M
authors.lastname: Plebanski
authors.forename: Bruce E
authors.initials: BE
authors.lastname: Loveland
authors.forename: Campbell
authors.initials: C
authors.lastname: Aitken
authors.forename: Simon
authors.initials: S
authors.lastname: Barry
authors.forename: Louis
authors.initials: L
authors.lastname: Schofield
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Gowans
mesh_terms: D000956:Antigens, Viral / Q000276:immunology*; D002469:Cell Separation; D044127:Epigenesis, Genetic; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D005434:Flow Cytometry; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000276:immunology*; D020869:Gene Expression Profiling; D019698:Hepatitis C, Chronic / Q000235:genetics / Q000276:immunology*; D006801:Humans; D057131:Immune Evasion / Q000276:immunology; D007108:Immune Tolerance / Q000276:immunology; D053645:Interleukin-2 Receptor alpha Subunit / Q000276:immunology; D020411:Oligonucleotide Array Sequence Analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
chemical_list: D000956:Antigens, Viral; D018984:Epitopes, T-Lymphocyte; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D053645:Interleukin-2 Receptor alpha Subunit