Histone Modulation Blocks Treg-Induced Foxp3 Binding to the IL-2 Promoter of Virus-Specific CD8+ T Cells from Feline Immunodeficiency Virus-Infected Cats
CD8+ T cells are critical for controlling HIV infection. During the chronic phase of lentiviral infection, CD8+ T cells lose their proliferative capacity and exhibit impaired antiviral function. This loss of CD8+ T cell function is due, in part, to CD4+CD25+ T regulatory (Treg) cell-mediated suppres...
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| Format: | Article |
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MDPI AG
2018-05-01
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| Series: | Viruses |
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| Online Access: | http://www.mdpi.com/1999-4915/10/6/287 |
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| author | Mukta Nag Yan Wang Kristina De Paris Jonathan E. Fogle |
| author_facet | Mukta Nag Yan Wang Kristina De Paris Jonathan E. Fogle |
| author_sort | Mukta Nag |
| collection | DOAJ |
| description | CD8+ T cells are critical for controlling HIV infection. During the chronic phase of lentiviral infection, CD8+ T cells lose their proliferative capacity and exhibit impaired antiviral function. This loss of CD8+ T cell function is due, in part, to CD4+CD25+ T regulatory (Treg) cell-mediated suppression. Our research group has demonstrated that lentivirus-activated CD4+CD25+ Treg cells induce the repressive transcription factor forkhead box P3 (Foxp3) in autologous CD8+ T cells following co-culture. We have recently reported that Treg-induced Foxp3 binds the interleukin-2 (IL-2), interferon-γ (IFN- γ), and tumor necrosis factor-α (TNF-α) promoters in virus-specific CD8+ T cells. These data suggest an important role of Foxp3-mediated CD8+ T cell dysfunction in lentiviral infection. To elucidate the mechanism of this suppression, we previously reported that decreased methylation facilitates Foxp3 binding in mitogen-activated CD8+ T cells from feline immunodeficiency virus (FIV)-infected cats. We demonstrated the reduced binding of Foxp3 to the IL-2 promoter by increasing methylation of CD8+ T cells. In the studies presented here, we ask if another form of epigenetic modulation might alleviate Foxp3-mediated suppression in CD8+ T cells. We hypothesized that decreasing histone acetylation in virus-specific CD8+ T cells would decrease Treg-induced Foxp3 binding to the IL-2 promoter. Indeed, using anacardic acid (AA), a known histone acetyl transferase (HAT) inhibitor, we demonstrate a reduction in Foxp3 binding to the IL-2 promoter in virus-specific CD8+ T cells co-cultured with autologous Treg cells. These data identify a novel mechanism of Foxp3-mediated CD8+ T cell dysfunction during lentiviral infection. |
| first_indexed | 2024-04-12T03:05:36Z |
| format | Article |
| id | doaj.art-fc5777ccc2044cb692129305b1903a40 |
| institution | Directory Open Access Journal |
| issn | 1999-4915 |
| language | English |
| last_indexed | 2024-04-12T03:05:36Z |
| publishDate | 2018-05-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Viruses |
| spelling | doaj.art-fc5777ccc2044cb692129305b1903a402022-12-22T03:50:31ZengMDPI AGViruses1999-49152018-05-0110628710.3390/v10060287v10060287Histone Modulation Blocks Treg-Induced Foxp3 Binding to the IL-2 Promoter of Virus-Specific CD8+ T Cells from Feline Immunodeficiency Virus-Infected CatsMukta Nag0Yan Wang1Kristina De Paris2Jonathan E. Fogle3Department of Population Health and Pathobiology, College of Veterinary Medicine, North Carolina State University, 1060 William Moore Drive, Raleigh, NC 27607, USADepartment of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USADepartment of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USADepartment of Population Health and Pathobiology, College of Veterinary Medicine, North Carolina State University, 1060 William Moore Drive, Raleigh, NC 27607, USACD8+ T cells are critical for controlling HIV infection. During the chronic phase of lentiviral infection, CD8+ T cells lose their proliferative capacity and exhibit impaired antiviral function. This loss of CD8+ T cell function is due, in part, to CD4+CD25+ T regulatory (Treg) cell-mediated suppression. Our research group has demonstrated that lentivirus-activated CD4+CD25+ Treg cells induce the repressive transcription factor forkhead box P3 (Foxp3) in autologous CD8+ T cells following co-culture. We have recently reported that Treg-induced Foxp3 binds the interleukin-2 (IL-2), interferon-γ (IFN- γ), and tumor necrosis factor-α (TNF-α) promoters in virus-specific CD8+ T cells. These data suggest an important role of Foxp3-mediated CD8+ T cell dysfunction in lentiviral infection. To elucidate the mechanism of this suppression, we previously reported that decreased methylation facilitates Foxp3 binding in mitogen-activated CD8+ T cells from feline immunodeficiency virus (FIV)-infected cats. We demonstrated the reduced binding of Foxp3 to the IL-2 promoter by increasing methylation of CD8+ T cells. In the studies presented here, we ask if another form of epigenetic modulation might alleviate Foxp3-mediated suppression in CD8+ T cells. We hypothesized that decreasing histone acetylation in virus-specific CD8+ T cells would decrease Treg-induced Foxp3 binding to the IL-2 promoter. Indeed, using anacardic acid (AA), a known histone acetyl transferase (HAT) inhibitor, we demonstrate a reduction in Foxp3 binding to the IL-2 promoter in virus-specific CD8+ T cells co-cultured with autologous Treg cells. These data identify a novel mechanism of Foxp3-mediated CD8+ T cell dysfunction during lentiviral infection.http://www.mdpi.com/1999-4915/10/6/287Feline Immunodeficiency VirusCD8+ T cellsCD8+ T cell dysfunctionT regulatory cellsTreg suppressionFoxp3IL-2 suppressionepigeneticshistone acetylation |
| spellingShingle | Mukta Nag Yan Wang Kristina De Paris Jonathan E. Fogle Histone Modulation Blocks Treg-Induced Foxp3 Binding to the IL-2 Promoter of Virus-Specific CD8+ T Cells from Feline Immunodeficiency Virus-Infected Cats Viruses Feline Immunodeficiency Virus CD8+ T cells CD8+ T cell dysfunction T regulatory cells Treg suppression Foxp3 IL-2 suppression epigenetics histone acetylation |
| title | Histone Modulation Blocks Treg-Induced Foxp3 Binding to the IL-2 Promoter of Virus-Specific CD8+ T Cells from Feline Immunodeficiency Virus-Infected Cats |
| title_full | Histone Modulation Blocks Treg-Induced Foxp3 Binding to the IL-2 Promoter of Virus-Specific CD8+ T Cells from Feline Immunodeficiency Virus-Infected Cats |
| title_fullStr | Histone Modulation Blocks Treg-Induced Foxp3 Binding to the IL-2 Promoter of Virus-Specific CD8+ T Cells from Feline Immunodeficiency Virus-Infected Cats |
| title_full_unstemmed | Histone Modulation Blocks Treg-Induced Foxp3 Binding to the IL-2 Promoter of Virus-Specific CD8+ T Cells from Feline Immunodeficiency Virus-Infected Cats |
| title_short | Histone Modulation Blocks Treg-Induced Foxp3 Binding to the IL-2 Promoter of Virus-Specific CD8+ T Cells from Feline Immunodeficiency Virus-Infected Cats |
| title_sort | histone modulation blocks treg induced foxp3 binding to the il 2 promoter of virus specific cd8 t cells from feline immunodeficiency virus infected cats |
| topic | Feline Immunodeficiency Virus CD8+ T cells CD8+ T cell dysfunction T regulatory cells Treg suppression Foxp3 IL-2 suppression epigenetics histone acetylation |
| url | http://www.mdpi.com/1999-4915/10/6/287 |
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