A single TCR antagonist peptide inhibits experimental allergic encephalomyelitis mediated by a diverse T cell repertoire.
A single TCR antagonist peptide inhibits experimental allergic encephalomyelitis mediated by a diverse T cell repertoire.
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DOI：
10.4049/jimmunol.153.7.3326
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发表时间：
1994-10
影响因子：
4.4
通讯作者：
V. Kuchroo;J. Greer;D. Kaul;G. Ishioka;A. Franco;A. Sette;R. Sobel;M. Lees
中科院分区：
文献类型：
--
作者：
V. Kuchroo;J. Greer;D. Kaul;G. Ishioka;A. Franco;A. Sette;R. Sobel;M. Lees
此前，从SJL小鼠中获得了6个对髓鞘蛋白脂质蛋白（PLP）139至151位肽段残基（HSLGKWLGHPDKF）的致脑炎决定簇具有特异性的T细胞克隆，并且发现它们使用不同的T细胞受体（TCR）基因。为了设计能够在体外干扰这些克隆的活化并在体内抑制实验性自身免疫性脑脊髓炎（EAE）的TCR拮抗肽，我们首先确定了致脑炎肽的TCR和主要组织相容性复合体（MHC）接触残基。分析表明，144位（色氨酸）和147位（组氨酸）残基是TCR结合位点，145位（亮氨酸）和148位（脯氨酸）残基对MHC II类（IAs）结合很重要。基于此信息，合成了一种肽类似物（144位亮氨酸/147位精氨酸），其中两个主要的TCR接触残基都被替换。这种类似物对一组PLP 139 - 151特异性T细胞克隆起到TCR拮抗剂的作用，其本身不会引发EAE，能阻断天然139 - 151肽诱导疾病的作用，并且如果在疾病的最初症状出现时给药，可阻止临床疾病的进展。因此，尽管PLP 139 - 151特异性克隆使用多种TCR基因，但一种单一的肽类似物能够干扰疾病进程。这种方法对于设计肽类似物应该是可行的，这些肽类似物可在致病性抗原已知且TCR使用多样的人类自身免疫性疾病中进行治疗效果的测试。
Previously, six T cell clones, which are specific for an encephalitogenic determinant of myelin proteolipid protein (PLP) peptide residues 139 to 151 (HSLGKWLGHPDKF), were derived from SJL mice and shown to use diverse TCR genes. To design TCR antagonist peptides that could interfere with the activation of these clones in vitro and inhibit experimental allergic encephalomyelitis (EAE) in vivo, we first determined the TCR and MHC contact residues of the encephalitogenic peptide. The analysis indicated that residues 144 (tryptophan) and 147 (histidine) were the TCR binding sites and that residues 145 (leucine) and 148 (proline) were important for MHC class II (IAs) binding. On the basis of this information, a peptide analogue (leucine 144/arginine 147), in which both of the major TCR contact residues were substituted, was synthesized. This analogue acts as a TCR antagonist for the panel of PLP 139-151-specific T cell clones, does not cause EAE by itself, blocks the induction of disease by the native 139-151 peptide, and prevents clinical disease progression if administered at the first signs of disease. Thus, although multiple TCR genes are used by PLP 139-151-specific clones, a single peptide analogue can interfere with the disease process. This approach should be feasible for designing peptide analogues that can be tested for therapeutic efficacy in human autoimmune diseases in which the pathogenic Ags are known and TCR use is diverse.