Suppression of human T-cell responses to β-cells by activation of B7-H4 pathway

被引:40
|
作者
Ou, Dawei
Wangj, Xiaojie
Metzger, Daniel L.
Ao, Ziliang
Pozzilli, Paolo
James, Roger F. L.
Chen, Lieping
Warnock, Garth L.
机构
[1] Univ British Columbia, Fac Med, Dept Surg, Vancouver, BC V5Z 1L8, Canada
[2] Univ British Columbia, Dept Pediat, Vancouver, BC V5Z 4H4, Canada
[3] St Bartholomews Hosp, Royal London Sch Med, London C1A 7BE, England
[4] Univ Leicester, Dept Infect Immunol & Inflammat, Leicester LE2 7LX, Leics, England
[5] Johns Hopkins Univ, Sch Med, Dept Dermatol & Oncol, Baltimore, MD 21205 USA
关键词
B7-H4; type; 1; diabetes; costimulatory molecules; suppression of T-cell responses; 5-cell destruction; islet cell transplantation;
D O I
10.3727/000000006783981837
中图分类号
Q813 [细胞工程];
学科分类号
摘要
B7-H4, a recently described member of the B7 family of cosignal molecules, is thought to be involved in the regulation of cellular and humoral immune responses through receptors on activated T and B cells. Human islet cells express positive B7-H4 mRNA in RT-PCR assays, but not B7-H4 protein on cell surface in flow cytometric analyses. To investigate the regulatory effects of activation of the B7-H4 pathway on the function of activated T cells of patients with type 1 diabetes (T1D), we have used our in vitro human experimental system, including human beta-cell antigen-specific T-cell clones and human beta-cell lines CM and HP62, as well as primary islet cells. B7-H4.Ig protein was purified from the culture supernatant of 293T cells transfected by a B7-H4.Ig plasmid (pMIgV, containing a human B7-H4 cDNA and a mouse IgG2a Fc cDNA). Our preliminary studies showed that immobilized fusion protein human B7-H4.Ig (coated with 5 mu g/ml for 2 h at 37 degrees C), but not control Ig, clearly inhibited the proliferation of activated CD4+ and CD8+ T cells of patients induced by anti-CD3 antibody in CFSE assays. B7-H4.Ig also arrested cell cycle progression of T cells in G(0)/G(1) phase and induced T-cell apoptosis as measured by BrdU-7-AAD flow cytometric analysis. To determine the cytoprotective effects of B7-H4, we developed transfectants of human beta-cell lines CM and HP62 and islet cells transfected with the B7-H4.Ig plasmid, using empty vector transfectants as controls. The results demonstrate that cell-associated B7-H4.Ig expressed on human beta-cells clearly inhibits the cytotoxicity of the T-cell clones to targeted human beta-cells in Cr-51 release cytotoxicity assays. Activation of the B7-H4 pathway may represent a novel immunotherapeutic approach to inhibit T-cell responses for the prevention of beta-cell destruction in T1D.
引用
收藏
页码:399 / 410
页数:12
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