Immune inhibitory function of bovine CTLA-4 and the effects of its blockade in IFN-γ production

被引：12

作者：

Watari, Kei ^{[1
]}

Konnai, Satoru ^{[1
,2
]}

Maekawa, Naoya ^{[1
,2
]}

Okagawa, Tomohiro ^{[1
,2
]}

Suzuki, Yasuhiko ^{[2
,3
,4
]}

Murata, Shiro ^{[1
,2
]}

Ohashi, Kazuhiko ^{[1
,2
]}

机构：

[1] Hokkaido Univ, Fac Vet Med, Dept Dis Control, Sapporo, Hokkaido 0600818, Japan

[2] Hokkaido Univ, Fac Vet Med, Dept Adv Pharmaceut, Sapporo, Hokkaido 0600818, Japan

[3] Hokkaido Univ, Res Ctr Zoonosis Control, Div Bioresources, Sapporo, Hokkaido 0010020, Japan

[4] Hokkaido Univ, Global Inst Collaborat Res & Educ GI CoRE, Global Stn Zoonosis Control, Sapporo, Hokkaido 0010020, Japan

来源：

BMC VETERINARY RESEARCH | 2019年 / 15卷 / 01期

基金：

日本学术振兴会;

关键词：

Cattle; CTLA-4; CD80; CD86; IFN-gamma; BLV; LEUKEMIA-VIRUS; T-CELLS; EXPRESSION ANALYSIS; MOLECULAR-CLONING;

D O I：

10.1186/s12917-019-2082-7

中图分类号：

S85 [动物医学（兽医学）];

学科分类号：

0906 ;

摘要：

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-gamma) 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-4Ig to both CD80 and CD86 in a dose-dependent manner. The bovine CTLA-4 mAb significantly restored the inhibited IFN-gamma production from the CTLA-4-Ig treated PBMCs. In addition, the CTLA-4 mAb significantly enhanced IFN-gamma 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-gamma 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.

引用

页数：10

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