Degenerate T-cell recognition of peptides on MHC molecules creates large holes in the T-cell repertoire.
Degenerate T-cell recognition of peptides on MHC molecules creates large holes in the T-cell repertoire.
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DOI：
10.1371/journal.pcbi.1002412
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发表时间：
2012
影响因子：
4.3
通讯作者：
Keşmir C
中科院分区：
文献类型：
--
作者：
Calis JJ;de Boer RJ;Keşmir C
细胞免疫系统筛选由宿主细胞在MHC分子上呈递的肽，以评估细胞是否被感染。在这项研究中，我们研究了所提出的肽是否包含足够的信息，通过比较大量的MHC分子上的人类（自我）和细菌或病毒（非自我）肽进行适当的自我/非自我评估。对于所有测试的MHC分子，只有一小部分的提出非自我肽从174种细菌和1000病毒蛋白质组（0.2%）被证明是相同的自我肽。接下来，我们使用T细胞受体-肽-MHC相互作用的可用数据来估计T细胞如何区分相似的肽。T细胞受体对肽-MHC的识别是灵活的，因此，预期约三分之一的呈递的非自身肽与呈递的自身肽（通过T细胞）是不可区分的。这表明T细胞预期对大部分呈递的非自身肽保持耐受性，这为大部分外源表位发现的“T细胞库中的孔”提供了解释。此外，这种与自身的重叠增加了对有效的自身耐受性的需求，因为许多自相似的非自身肽可以启动自身免疫应答。因此，T细胞对肽-MHC-I复合物的简并识别在自体和非自体之间产生了巨大的和潜在危险的重叠。人类细胞从内源性蛋白质中提取短肽，并通过细胞表面的HLA I类分子将其呈递给免疫系统。T细胞扫描呈递的肽，并且需要区分外来（非自身）肽与人类（自身）肽。我们表明，这是一项艰巨的任务，尽管T细胞的精致特异性。我们估计，使用HLA-肽结合预测和T细胞识别模型，几乎三分之一的非自身肽-HLA复合物是如此相似的自身肽-HLA，T细胞不能区分它们。由于T细胞必须忽略自身肽以防止自身免疫，我们估计至少有三分之一的外源肽也必须被忽略，因此无法引起免疫应答。从未用于免疫应答的外源肽被称为“库中的孔”。由于我们预测的洞的大小与以前发现的一致，我们的猜测是，洞完全是由于与自身肽的相似性。我们测试这个猜想与HIV-1和牛痘反应的公开数据，并确认自我相似性是一个主要的决定因素的免疫反应非自我肽。
The cellular immune system screens peptides presented by host cells on MHC molecules to assess if the cells are infected. In this study we examined whether the presented peptides contain enough information for a proper self/nonself assessment by comparing the presented human (self) and bacterial or viral (nonself) peptides on a large number of MHC molecules. For all MHC molecules tested, only a small fraction of the presented nonself peptides from 174 species of bacteria and 1000 viral proteomes (0.2%) is shown to be identical to a presented self peptide. Next, we use available data on T-cell receptor-peptide-MHC interactions to estimate how well T-cells distinguish between similar peptides. The recognition of a peptide-MHC by the T-cell receptor is flexible, and as a result, about one-third of the presented nonself peptides is expected to be indistinguishable (by T-cells) from presented self peptides. This suggests that T-cells are expected to remain tolerant for a large fraction of the presented nonself peptides, which provides an explanation for the “holes in the T-cell repertoire” that are found for a large fraction of foreign epitopes. Additionally, this overlap with self increases the need for efficient self tolerance, as many self-similar nonself peptides could initiate an autoimmune response. Degenerate recognition of peptide-MHC-I complexes by T-cells thus creates large and potentially dangerous overlaps between self and nonself. Human cells sample short peptides from endogenous proteins, and present them to the immune system via HLA class I molecules on the cell surface. T-cells scan the presented peptides and need to discriminate foreign (nonself) peptides from human (self) peptides. We show that this is a difficult task, despite the exquisite specificity of T-cells. We estimate, using HLA-peptide binding predictions and T-cell recognition models, that almost a third of the nonself peptide-HLA complexes is so similar to a self peptide-HLA that a T-cell cannot tell them apart. Since T-cells have to ignore self peptides to prevent autoimmunity, we estimate that at least a third of the foreign peptides has to be ignored as well, and therefore fails to evoke an immune response. Foreign peptides that are never used in immune responses, have been referred to as the “holes in the repertoire”. Since the sizes of the holes we predict agree with those that were previously found, our conjecture is that the holes are entirely due to similarity with self peptides. We test this conjecture with public data on HIV-1 and vaccinia responses, and confirm that self similarity is a major determinant of the immune response to nonself peptides.
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DOI：
10.1084/jem.20001021
发表时间：
2002-03-04
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Blattman JN;Antia R;Sourdive DJ;Wang X;Kaech SM;Murali-Krishna K;Altman JD;Ahmed R
通讯作者：
Ahmed R
影响因子：
2.6
作者：
Gough SC;Simmonds MJ
通讯作者：
Simmonds MJ
影响因子：
4.4
作者：
Hoof, Ilka;Perez, Carina L.;Karlsson, Annika C.
通讯作者：
Karlsson, Annika C.
影响因子：
3.2
作者：
Burroughs, NJ;de Boer, RJ;Kesmir, C
通讯作者：
Kesmir, C
DOI：
10.1111/j.1463-1326.2008.01001.x
发表时间：
2009-02
期刊：
Diabetes, obesity & metabolism
影响因子：
--
作者：
Howson JM;Walker NM;Clayton D;Todd JA;Type 1 Diabetes Genetics Consortium
通讯作者：
Type 1 Diabetes Genetics Consortium