Parallel Expansion of Human Virus-Specific FoxP3− Effector Memory and De Novo-Generated FoxP3+ Regulatory CD8+ T Cells upon Antigen Recognition In Vitro

Abstract

Although FoxP3 has been shown to be the most specific marker for regulatory CD4+ T cells, its significance in the CD8+ T cell population is not well understood. In this study, we show that the in vitro stimulation of human PBMC with hepatitis C virus or Flu virus-specific peptides gives rise to two distinct Ag-specific T cell populations: FoxP3− and FoxP3+CD8+ T cells. The FoxP3+ virus-specific CD8+ T cells share phenotypical markers of regulatory T cells, such as CTLA-4 and glucocorticoid-induced TNFR family-related gene, and do produce moderate amounts of IFN-γ but not IL-2 or IL-10. IL-2 and IL-10 are critical cytokines, however, because the expansion of virus-specific FoxP3+CD8+ T cells is blocked by IL-2- or IL-10-neutralizing mAbs. The virus-specific FoxP3+CD8+ T cells have a reduced proliferative capacity, indicating anergy, and display a cell-cell contact-dependent suppressive activity. Taken together, our results indicate that stimulation with a defined viral Ag leads to the expansion of two different cell populations: FoxP3− memory/effector as well as FoxP3+ regulatory virus-specific CD8+ T cells.

Prediction of Reactivity to Noninherited Maternal Antigen in MHC-Mismatched, Minor Histocompatibility Antigen-Matched Stem Cell Transplantation in a Mouse Model

“…Although Foxp3 is not a very specific marker for regulatory T cells given that activated nonregulatory T cells may transiently upregulate this transcription factor (34,35), several reports and current data described that regulatory T cells mediate tolerance to NIMA (31,36).…”

Determinants of in vitro expansion of different human virus-specific FoxP3+ regulatory CD8+ T cells in chronic hepatitis C virus infection

“…PBMCs were stimulated and analysed as described previously (Billerbeck et al, 2007) by using Tetramer and antibody staining, and intracellular FoxP3 staining. Cells were stained with HLA-A2 tetramers and surface antibodies as described previously (Billerbeck et al, 2007).…”

“…PBMCs were stimulated and analysed as described previously (Billerbeck et al, 2007) by using Tetramer and antibody staining, and intracellular FoxP3 staining. Cells were stained with HLA-A2 tetramers and surface antibodies as described previously (Billerbeck et al, 2007). Intracellular FoxP3 staining was performed by using the eBioscience FoxP3 staining buffer set for antibody PCH101 or the BioLegend FoxP3 Flow kit for antibody 259D according to the manufacturers' instructions.…”

“…For example, in chronic human immunodeficiency virus (HIV) and hepatitis C virus (HCV) infection, IL-10-or TGF-b-producing regulatory CD8 + T cells that suppress cytokine production and proliferation of T cells have been identified (Accapezzato et al, 2004;Alatrakchi et al, 2007;Garba et al, 2002). We have recently shown that the in vitro stimulation of human peripheral blood mononuclear cells (PBMCs) with HCVand influenza virus (FLU)-specific peptides results in the parallel expansion of two distinct virus-specific CD8 + T-cell populations: FoxP3 2 effector CD8 + T cells and FoxP3 + regulatory CD8 + T cells, which display a suppressive activity (Billerbeck et al, 2007).…”

Correlation of clinical and virologic responses to antiviral treatment and regulatory T cell evolution in patients with hepatitis C virus–induced mixed cryoglobulinemia vasculitis

“…It has also been shown that CD8ϩ cells from patients with chronic HCV infection may express FoxP3 after stimulation with HCV-derived peptides, which indicates that there is likely a wide heterogeneity of FoxP3-expressing cells in response to viral infection (30). Moreover, our finding that a complete response to treatment with PEGylated interferon alfa-2b plus ribavirin was associated with a decrease in T cell activation, contrasts to some degree with previous studies in patients with chronic HCV infection without MC, which showed that treatment with interferon plus ribavirin induced an increase in T cell activation markers (HLAϪDRϩ and CD25ϩ) after treatment (31), as well as a shift toward a Th1-type response (32)(33)(34).…”