title: Identification and in vitro expansion of functional antigen-specific CD25+ FoxP3+ regulatory T cells in hepatitis C virus infection.
abstract: CD4(+)CD25(+) regulatory T cells (CD25(+) Tregs) play a key role in immune regulation. Since hepatitis C virus (HCV) persists with increased circulating CD4(+)CD25(+) T cells and virus-specific effector T-cell dysfunction, we asked if CD4(+)CD25(+) T cells in HCV-infected individuals are similar to natural Tregs in uninfected individuals and if they include HCV-specific Tregs using the specific Treg marker FoxP3 at the single-cell level. We report that HCV-infected patients display increased circulating FoxP3(+) Tregs that are phenotypically and functionally indistinguishable from FoxP3(+) Tregs in uninfected subjects. Furthermore, HCV-specific FoxP3(+) Tregs were detected in HCV-seropositive persons with antigen-specific expansion, major histocompatibility complex class II/peptide tetramer binding affinity, and preferential suppression of HCV-specific CD8 T cells. Transforming growth factor beta contributed to antigen-specific Treg expansion in vitro, suggesting that it may contribute to antigen-specific Treg expansion in vivo. Interestingly, FoxP3 expression was also detected in influenza virus-specific CD4 T cells. In conclusion, functionally active and virus-specific FoxP3(+) Tregs are induced in HCV infection, thus providing targeted immune regulation in vivo. Detection of FoxP3 expression in non-HCV-specific CD4 T cells suggests that immune regulation through antigen-specific Treg induction extends beyond HCV.
authors.affiliation: Philadelphia Veterans Affairs Medical Center, Philadelphia, PA 19104, USA.
authors.forename: Hirotoshi
authors.initials: H
authors.lastname: Ebinuma
authors.forename: Nobuhiro
authors.initials: N
authors.lastname: Nakamoto
authors.forename: Yun
authors.initials: Y
authors.lastname: Li
authors.forename: David A
authors.initials: DA
authors.lastname: Price
authors.forename: Emma
authors.initials: E
authors.lastname: Gostick
authors.forename: Bruce L
authors.initials: BL
authors.lastname: Levine
authors.forename: J
authors.initials: J
authors.lastname: Tobias
authors.forename: William W
authors.initials: WW
authors.lastname: Kwok
authors.forename: Kyong-Mi
authors.initials: KM
authors.lastname: Chang
mesh_terms: D015704:CD4 Antigens / Q000032:analysis; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D049109:Cell Proliferation; D002478:Cells, Cultured; D005434:Flow Cytometry; D051858:Forkhead Transcription Factors / Q000032:analysis*; D016174:Hepacivirus / Q000276:immunology*; D006526:Hepatitis C / Q000276:immunology*; D000949:Histocompatibility Antigens Class II / Q000378:metabolism; D006801:Humans; D053645:Interleukin-2 Receptor alpha Subunit / Q000032:analysis*; D011485:Protein Binding; D016176:T-Lymphocyte Subsets / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000737:chemistry / Q000276:immunology*; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D015704:CD4 Antigens; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D000949:Histocompatibility Antigens Class II; D053645:Interleukin-2 Receptor alpha Subunit; D016212:Transforming Growth Factor beta