A single autoimmune T cell receptor recognizes more than a million different peptides.
A single autoimmune T cell receptor recognizes more than a million different peptides.
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DOI：
10.1074/jbc.m111.289488
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发表时间：
2012-01-06
期刊：
影响因子：
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通讯作者：
Sewell AK
中科院分区：
文献类型：
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作者：
Wooldridge L;Ekeruche-Makinde J;van den Berg HA;Skowera A;Miles JJ;Tan MP;Dolton G;Clement M;Llewellyn-Lacey S;Price DA;Peakman M;Sewell AK
背景：有限的<108 T细胞受体（TCRs）如何提供对bb1015抗原的免疫？结果：单个TCR可对100万种不同的十聚体肽产生反应。结论：这种史无前例的受体混杂解释了naïve TCR库如何获得有效的免疫。意义：TCR变性极有可能成为自身免疫性疾病的根本原因。在主要组织相容性复合体（MHC）分子的背景下，T细胞受体（TCR）通过与细胞表面呈现的外源肽结合来协调免疫反应。有效的免疫需要所有可能的外源肽- mhc分子被识别，否则就有可能在免疫覆盖上留下漏洞，病原体可能会迅速进化来利用这些漏洞。目前尚不清楚的是，有限的<108人tcr如何成功地对20种蛋白质原氨基酸产生的大量可能不同的肽提供免疫，这些肽可由自身mhc分子（bbb1015种不同的肽- mhc）呈现。一种可能是T细胞免疫结合了极高水平的受体退化，使每个TCR能够识别多种肽。然而，这种TCR退化的程度从未被完全量化。在这里，我们进行了全面的实验和数学分析，以揭示单个患者来源的自身免疫性CD8+ T细胞克隆与人类I型糖尿病的致病相关，在单个MHC I类分子的背景下识别bbb100万个不同的十聚体肽。我们发现了大量比野生型“指数”胰岛素原衍生肽（ALWGPDPAAA）更好的激动剂。RQFGPDFPTI肽（从>08个肽中取样）比索引肽的效力高>100倍，尽管在10个位置中有7个与该序列不同。量化这种以前未被认识到的高水平CD8+ T细胞交叉反应性是理解适应性免疫系统需求的重要一步，并强调了TCR变性作为自身免疫性疾病致病因素的巨大潜力。
Background: How does a limited pool of <108 T cell receptors (TCRs) provide immunity to >1015 antigens? Results: A single TCR can respond to >one million different decamer peptides. Conclusion: This unprecedented level of receptor promiscuity explains how the naïve TCR repertoire achieves effective immunity. Significance: TCR degeneracy has enormous potential to be the root cause of autoimmune disease. The T cell receptor (TCR) orchestrates immune responses by binding to foreign peptides presented at the cell surface in the context of major histocompatibility complex (MHC) molecules. Effective immunity requires that all possible foreign peptide-MHC molecules are recognized or risks leaving holes in immune coverage that pathogens could quickly evolve to exploit. It is unclear how a limited pool of <108 human TCRs can successfully provide immunity to the vast array of possible different peptides that could be produced from 20 proteogenic amino acids and presented by self-MHC molecules (>1015 distinct peptide-MHCs). One possibility is that T cell immunity incorporates an extremely high level of receptor degeneracy, enabling each TCR to recognize multiple peptides. However, the extent of such TCR degeneracy has never been fully quantified. Here, we perform a comprehensive experimental and mathematical analysis to reveal that a single patient-derived autoimmune CD8+ T cell clone of pathogenic relevance in human type I diabetes recognizes >one million distinct decamer peptides in the context of a single MHC class I molecule. A large number of peptides that acted as substantially better agonists than the wild-type “index” preproinsulin-derived peptide (ALWGPDPAAA) were identified. The RQFGPDFPTI peptide (sampled from >108 peptides) was >100-fold more potent than the index peptide despite differing from this sequence at 7 of 10 positions. Quantification of this previously unappreciated high level of CD8+ T cell cross-reactivity represents an important step toward understanding the system requirements for adaptive immunity and highlights the enormous potential of TCR degeneracy to be the causative factor in autoimmune disease.