Vaccination with single chain antigen receptors for islet-derived peptides presented on I-A(g7) delays diabetes in NOD mice by inducing anergy in self-reactiveT-cells.
Vaccination with single chain antigen receptors for islet-derived peptides presented on I-A(g7) delays diabetes in NOD mice by inducing anergy in self-reactiveT-cells.
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DOI：
10.1371/journal.pone.0069464
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Sherwin R
中科院分区：
文献类型：
--
作者：
Gurr W;Shaw M;Herzog RI;Li Y;Sherwin R
为了开发一种预防1型糖尿病（T1 D）的疫苗接种方法，选择性地减弱针对特定自身抗原的自身反应性T细胞，我们选择了噬菌体展示的单链抗原受体文库，用于结合NOD II类MHC I-Ag 7和胰岛自身抗原RegII衍生的表位的复合物的克隆。从用RegII脉冲的NOD抗原呈递细胞免疫的II类错配小鼠的B细胞受体库或从NOD小鼠的胰腺淋巴结中的T细胞受体库产生文库。这两种方法都产生了在I-Ag 7的背景下识别RegII衍生表位的克隆，其激活自身反应性CD 4 + T细胞。通过将BDC2.5TCR转化为单链形式，获得具有不同特异性的受体。如果糖尿病诱导细胞和单链受体的特异性相匹配，则来自接种克隆的供体的B细胞而不是T细胞将糖尿病保护转移到NOD-SCID受体。来自用BDC2.5单链受体接种的供体的B细胞和抗体在BDC2.5 TCR转基因NOD受体的T细胞中诱导了严重的无反应性状态，而来自用对I-Ag 7 RegII肽复合物特异性的单链受体接种的供体的B细胞仅诱导了部分无反应性。用识别I-Ag 7 RegII肽复合物的受体或用BDC2.5单链受体接种正常NOD小鼠延迟T1 D的发作。因此，抗独特型疫苗接种可以成功地应用于T1 D，疫苗由自身反应性T细胞克隆产生或来源于抗原受体文库。
To develop a vaccination approach for prevention of type 1 diabetes (T1D) that selectively attenuates self-reactive T-cells targeting specific autoantigens, we selected phage-displayed single chain antigen receptor libraries for clones binding to a complex of the NOD classII MHC I-Ag7 and epitopes derived from the islet autoantigen RegII. Libraries were generated from B-cell receptor repertoires of classII-mismatched mice immunized with RegII-pulsed NOD antigen presenting cells or from T-cell receptor repertoires in pancreatic lymph nodes of NOD mice. Both approaches yielded clones recognizing a RegII-derived epitope in the context of I-Ag7, which activated autoreactive CD4+ T-cells. A receptor with different specificity was obtained by converting the BDC2.5 TCR into single chain form. B- but not T-cells from donors vaccinated with the clones transferred protection from diabetes to NOD-SCID recipients if the specificity of the diabetes inducer cell and the single chain receptor were matched. B-cells and antibodies from donors vaccinated with the BDC2.5 single chain receptor induced a state of profound anergy in T-cells of BDC2.5 TCR transgenic NOD recipients while B-cells from donors vaccinated with a single chain receptor specific for I-Ag7 RegII peptide complexes induced only partial non-responsiveness. Vaccination of normal NOD mice with receptors recognizing I-Ag7 RegII peptide complexes or with the BDC2.5 single chain receptor delayed onset of T1D. Thus anti-idiotypic vaccination can be successfully applied to T1D with vaccines either generated from self-reactive T-cell clones or derived from antigen receptor libraries.
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