Immune inhibitory function of bovine CTLA-4 and the effects of its blockade in IFN-γ production
Abstract Background Cytotoxic T-lymphocyte antigen 4 (CTLA-4) is known as an immune inhibitory receptor that is expressed on activated effector T cells and regulatory T cells. When CTLA-4 binds to CD80 or CD86, immunoinhibitory signals are transmitted to retain a homeostasis of the immune response....
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doaj-2f68fdfc9528402a9ef76f97c4ac28562020-11-25T03:41:23ZengBMCBMC Veterinary Research1746-61482019-10-0115111010.1186/s12917-019-2082-7Immune inhibitory function of bovine CTLA-4 and the effects of its blockade in IFN-γ productionKei Watari0Satoru Konnai1Naoya Maekawa2Tomohiro Okagawa3Yasuhiko Suzuki4Shiro Murata5Kazuhiko Ohashi6Department of Disease Control, Faculty of Veterinary Medicine, Hokkaido UniversityDepartment of Disease Control, Faculty of Veterinary Medicine, Hokkaido UniversityDepartment of Disease Control, Faculty of Veterinary Medicine, Hokkaido UniversityDepartment of Disease Control, Faculty of Veterinary Medicine, Hokkaido UniversityDepartment of Advanced Pharmaceutics, Faculty of Veterinary Medicine, Hokkaido UniversityDepartment of Disease Control, Faculty of Veterinary Medicine, Hokkaido UniversityDepartment of Disease Control, Faculty of Veterinary Medicine, Hokkaido UniversityAbstract Background Cytotoxic T-lymphocyte antigen 4 (CTLA-4) is known as an immune inhibitory receptor that is expressed on activated effector T cells and regulatory T cells. When CTLA-4 binds to CD80 or CD86, immunoinhibitory signals are transmitted to retain a homeostasis of the immune response. Recent studies have reported that CTLA-4 is upregulated in chronic infections and malignant neoplasms, contributing to host immune dysfunction. On the other hand, the blockade of CTLA-4 and CD80 or CD86 binding by antibody restores the immune response against these diseases. In a previous report, we indicated that the expression of CTLA-4 was closely associated with disease progression in cattle infected with the bovine leukemia virus (BLV). In this study, we established an anti-bovine CTLA-4 antibody to confirm its immune enhancing effect. Results Bovine CTLA-4-Ig binds to bovine CD80 and CD86 expressing cells. Additionally, CD80 and CD86 bind to CTLA-4 expressing cells in an expression-dependent manner. Bovine CTLA-4-Ig significantly inhibited interferon-gamma (IFN-γ) production from bovine peripheral blood mononuclear cells (PBMCs) activated by Staphylococcus enterotoxin B (SEB). An established specific monoclonal antibody (mAb) for bovine CTLA-4 specifically recognized only with bovine CTLA-4, not CD28, and the antibody blocked the binding of CTLA-4-Ig to both CD80 and CD86 in a dose-dependent manner. The bovine CTLA-4 mAb significantly restored the inhibited IFN-γ production from the CTLA-4-Ig treated PBMCs. In addition, the CTLA-4 mAb significantly enhanced IFN-γ production from CTLA-4 expressing PBMCs activated by SEB. Finally, we examined whether a CTLA-4 blockade by CTLA-4 mAb could restore the immune reaction during chronic infection; the blockade assay was performed using PBMCs from BLV-infected cattle. The CTLA-4 blockade enhanced IFN-γ production from the PBMCs in response to BLV-antigens. Conclusions Collectively, these results suggest that anti-bovine CTLA-4 antibody can reactivate lymphocyte functions and could be applied for a new therapy against refractory chronic diseases. Further investigation is required for future clinical applications.http://link.springer.com/article/10.1186/s12917-019-2082-7CattleCTLA-4CD80CD86IFN-γBLV |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Kei Watari Satoru Konnai Naoya Maekawa Tomohiro Okagawa Yasuhiko Suzuki Shiro Murata Kazuhiko Ohashi |
spellingShingle |
Kei Watari Satoru Konnai Naoya Maekawa Tomohiro Okagawa Yasuhiko Suzuki Shiro Murata Kazuhiko Ohashi Immune inhibitory function of bovine CTLA-4 and the effects of its blockade in IFN-γ production BMC Veterinary Research Cattle CTLA-4 CD80 CD86 IFN-γ BLV |
author_facet |
Kei Watari Satoru Konnai Naoya Maekawa Tomohiro Okagawa Yasuhiko Suzuki Shiro Murata Kazuhiko Ohashi |
author_sort |
Kei Watari |
title |
Immune inhibitory function of bovine CTLA-4 and the effects of its blockade in IFN-γ production |
title_short |
Immune inhibitory function of bovine CTLA-4 and the effects of its blockade in IFN-γ production |
title_full |
Immune inhibitory function of bovine CTLA-4 and the effects of its blockade in IFN-γ production |
title_fullStr |
Immune inhibitory function of bovine CTLA-4 and the effects of its blockade in IFN-γ production |
title_full_unstemmed |
Immune inhibitory function of bovine CTLA-4 and the effects of its blockade in IFN-γ production |
title_sort |
immune inhibitory function of bovine ctla-4 and the effects of its blockade in ifn-γ production |
publisher |
BMC |
series |
BMC Veterinary Research |
issn |
1746-6148 |
publishDate |
2019-10-01 |
description |
Abstract Background Cytotoxic T-lymphocyte antigen 4 (CTLA-4) is known as an immune inhibitory receptor that is expressed on activated effector T cells and regulatory T cells. When CTLA-4 binds to CD80 or CD86, immunoinhibitory signals are transmitted to retain a homeostasis of the immune response. Recent studies have reported that CTLA-4 is upregulated in chronic infections and malignant neoplasms, contributing to host immune dysfunction. On the other hand, the blockade of CTLA-4 and CD80 or CD86 binding by antibody restores the immune response against these diseases. In a previous report, we indicated that the expression of CTLA-4 was closely associated with disease progression in cattle infected with the bovine leukemia virus (BLV). In this study, we established an anti-bovine CTLA-4 antibody to confirm its immune enhancing effect. Results Bovine CTLA-4-Ig binds to bovine CD80 and CD86 expressing cells. Additionally, CD80 and CD86 bind to CTLA-4 expressing cells in an expression-dependent manner. Bovine CTLA-4-Ig significantly inhibited interferon-gamma (IFN-γ) production from bovine peripheral blood mononuclear cells (PBMCs) activated by Staphylococcus enterotoxin B (SEB). An established specific monoclonal antibody (mAb) for bovine CTLA-4 specifically recognized only with bovine CTLA-4, not CD28, and the antibody blocked the binding of CTLA-4-Ig to both CD80 and CD86 in a dose-dependent manner. The bovine CTLA-4 mAb significantly restored the inhibited IFN-γ production from the CTLA-4-Ig treated PBMCs. In addition, the CTLA-4 mAb significantly enhanced IFN-γ production from CTLA-4 expressing PBMCs activated by SEB. Finally, we examined whether a CTLA-4 blockade by CTLA-4 mAb could restore the immune reaction during chronic infection; the blockade assay was performed using PBMCs from BLV-infected cattle. The CTLA-4 blockade enhanced IFN-γ production from the PBMCs in response to BLV-antigens. Conclusions Collectively, these results suggest that anti-bovine CTLA-4 antibody can reactivate lymphocyte functions and could be applied for a new therapy against refractory chronic diseases. Further investigation is required for future clinical applications. |
topic |
Cattle CTLA-4 CD80 CD86 IFN-γ BLV |
url |
http://link.springer.com/article/10.1186/s12917-019-2082-7 |
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