Presentation of a T cell receptor antagonist peptide by immunoglobulins ablates activation of T cells by a synthetic peptide or proteins requiring endocytic processing.
Presentation of a T cell receptor antagonist peptide by immunoglobulins ablates activation of T cells by a synthetic peptide or proteins requiring endocytic processing.
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免疫球蛋白通过合成肽或需要内吞加工的蛋白质呈现T细胞受体拮抗剂肽的肽消融T细胞的激活。
DOI：
10.1084/jem.185.6.1043
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发表时间：
1997-03-17
期刊：
影响因子：
--
通讯作者：
Zaghouani H
中科院分区：
文献类型：
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作者：
Legge KL;Min B;Potter NT;Zaghouani H
T细胞受体（TCR）拮抗作用被认为是用于灭活侵袭性T细胞和逆转T细胞介导的自身免疫性疾病。TCR拮抗肽沉默攻击性T细胞和逆转游离肽诱导的实验性过敏性脑脊髓炎。然而，尚不清楚游离拮抗剂肽是否可以逆转天然疾病，其中抗原可能可用于内吞加工，并且肽获得新合成的II类MHC分子。使用有效的内吞呈递系统，我们证明了蛋白脂质蛋白（PLP）TCR拮抗剂肽（PLP-LR）上提出的IG分子（IgPLP-LR）废除激活的T细胞刺激与游离致脑炎PLP肽（PLP1），天然PLP，或含有PLP1肽（Ig-PLP1）的IG。当刺激物是游离PLP1肽时，游离PLP-LR消除T细胞活化，但当刺激物是天然PLP或Ig-PLP1时没有可测量的作用。在体内，Ig-PLP1诱导T细胞对PLP1肽的应答。然而，当与Ig-PLP-LR共同给药时，对PLP1肽的应答显著降低，而对PLP-LR的应答正常。与Ig-PLP1共同施用的游离PLP-LR对T细胞对PLP1的应答没有影响。这些发现表明，由IG的拮抗剂肽的内吞呈递胜过外部激动剂肽和内吞激动剂肽，而游离拮抗剂阻碍外部激动剂肽，但不阻碍内吞激动剂肽。与拮抗剂配体的直接接触和/或PLP-LR特异性T细胞的反式调节可能是Ig-PLP-LR介导的体内PLP 1特异性T细胞下调的作用机制。拮抗剂肽的有效内吞呈递，这是任一机制的基本事件，可能是逆转自发性T细胞介导的自身免疫性疾病的关键，其中持续的内吞抗原加工可能是T细胞攻击性的原因。
T cell receptor (TCR) antagonism is being considered for inactivation of aggressive T cells and reversal of T cell–mediated autoimmune diseases. TCR antagonist peptides silence aggressive T cells and reverse experimental allergic encephalomyelitis induced with free peptides. However, it is not clear whether free antagonist peptides could reverse natural disease where the antigen is presumably available for endocytic processing and peptides gain access to newly synthesized class II MHC molecules. Using an efficient endocytic presentation system, we demonstrate that a proteolipid protein (PLP) TCR antagonist peptide (PLP-LR) presented on an Ig molecule (IgPLP-LR) abrogates the activation of T cells stimulated with free encephalitogenic PLP peptide (PLP1), native PLP, or an Ig containing PLP1 peptide (Ig-PLP1). Free PLP-LR abolishes T cell activation when the stimulator is free PLP1 peptide, but has no measurable effect when the stimulator is the native PLP or Ig-PLP1. In vivo, Ig-PLP1 induces a T cell response to PLP1 peptide. However, when coadministered with Ig-PLP-LR, the response to PLP1 peptide is markedly reduced whereas the response to PLP-LR is normal. Free PLP-LR coadministered with Ig-PLP1 has no effect on the T cell response to PLP1. These findings indicate that endocytic presentation of an antagonist peptide by Ig outcompete both external and endocytic agonist peptides whereas free antagonist hinders external but not endocytic agonist peptide. Direct contact with antagonist ligand and/or trans-regulation by PLP-LR–specific T cells may be the operative mechanism for Ig-PLP-LR–mediated downregulation of PLP1-specific T cells in vivo. Efficient endocytic presentation of antagonist peptides, which is the fundamental event for either mechanism, may be critical for reversal of spontaneous T cell–mediated autoimmune diseases where incessant endocytic antigen processing could be responsible for T cell aggressivity.