T-CELL RECEPTOR REPERTOIRE FOR A VIRAL EPITOPE IN HUMANS IS DIVERSIFIED BY TOLERANCE TO A BACKGROUND MAJOR HISTOCOMPATIBILITY COMPLEX ANTIGEN
T-CELL RECEPTOR REPERTOIRE FOR A VIRAL EPITOPE IN HUMANS IS DIVERSIFIED BY TOLERANCE TO A BACKGROUND MAJOR HISTOCOMPATIBILITY COMPLEX ANTIGEN
复制标题
DOI：
10.1084/jem.182.6.1703
复制
发表时间：
1995-12-01
影响因子：
15.3
通讯作者：
ARGAET, VP
中科院分区：
文献类型：
--
作者：
BURROWS, SR;SILINS, SL;ARGAET, VP
对免疫显性EB病毒（EBV）表位FLRGRAYGL（与HLA B8相关）的记忆应答的两个不寻常的特征为研究人类的自身耐受性和T细胞受体（TCR）可塑性提供了独特的机会。首先，应答是特别受限的，由具有相同TCR蛋白序列的细胞毒性T淋巴细胞（CTL）主导（Argaet，V. P.，C. W.施密特，S. R. Burrows，S. L. Silins，M. G. Kurilla，D. L. Doolan，A. Suhrbier，D. J. Moss，E.基夫·T B。斯卡利和我S. Misko。1994. J失效Med，180：2335-2340）。其次，表达该受体的CTL与未感染细胞上的同种异体抗原HLA B*4402交叉反应（Burrows，S.二、R.卡纳Burrows和D. J·莫斯1994. J. Exp.男人179：1155-1161）。使用这种保守的公共TCR的CTL不能从表达HLA B8和B*4402两者的暴露于EBV的个体的外周血中再活化，这证明了人中潜在的自身反应性T细胞的克隆失活。一个显着的FLRGRAYGL特异性反应仍然是明显的，但是，和多个CTL克隆的TCR序列分析揭示了寡克隆TCR库内的这些个人，使用不同的V和J基因片段和CDR 3区的决定因素。此外，还鉴定了一种重要的公共TCR组分，其中来自许多无关HLA B8（+）、B*4402（+）供体的CTL克隆共享几种不同的α/β重排。公共TCR在对该EBV表位的应答中的显著优势表明TCR基因重组中存在强烈的遗传偏倚。使用肽类似物的精细特异性分析表明，FLRGRAYGL/HLA B8的六种不同抗原受体中，没有一种与肽的全部潜在TCR接触残基紧密相关。尽管HLA B*4402交叉反应性受体结合肽的COOH末端的氨基酸，但其他受体优先青睐NH 2末端决定簇，推测避开模拟HLA B*4402上呈现的结构的区域。因此，对背景主要组织相容性抗原的耐受性可以通过使应答远离TCR结合残基的免疫显性组合来有效地使针对外源表位的TCR库多样化。
Two unusual characteristics of the memory response to the immunodominant Epstein-Barr virus (EBV) epitope FLRGRAYGL, which associates with HLA B8, have provided an unique opportunity to investigate self tolerance and T cell receptor (TCR) plasticity in humans. First, the response is exceptionally restricted, dominated by cytotoxic T lymphocytes (CTL) with identical TCR protein sequences (Argaet, V. P., C. W. Schmidt, S. R. Burrows, S. L. Silins, M. G. Kurilla, D. L. Doolan, A. Suhrbier, D. J. Moss, E. Kieff T. B. Sculley, and I. S. Misko. 1994. J Exp. Med, 180:2335-2340). Second, CTL expressing this receptor are cross-reactive with the alloantigen HLA B*4402 on uninfected cells (Burrows, S. Ii., R. Khanna, J. M. Burrows, and D. J. Moss. 1994. J. Exp. Men. 179:1155-1161). No CTL using this conserved public TCR could be reactivated from the peripheral blood of EBV exposed individuals expressing both HLA B8 and B*4402, demonstrating the clonal inactivation of potentially self-reactive T cells in humans. A significant FLRGRAYGL-specific response was still apparent, however, and TCR sequence analysis of multiple CTL clones revealed an oligoclonal TCR repertoire for this determinant within these individuals, using diverse V and J gene segments and CDR3 regions. In addition, a significant public TCR component was identified in which several distinct alpha/beta rearrangements are shared by CTL clones from a number of unrelated HLA B8(+), B*4402(+) donors. The striking dominance of public TCR in the response to this EBV epitope suggests a strong genetic bias in TCR gene recombination. Fine specificity analysis using peptide analogues showed that, of six different antigen receptors for FLRGRAYGL/HLA B8, none associate closely with the peptide's full array of potential TCR contact residues. Whereas the HLA B*4402-cross-reactive receptor binds amino acids toward the COOH terminus of the peptide, others preferentially favor an NH2-terminal determinant, presumably evading an area that mimics a structure presented on HLA B*4402. Thus, tolerance to a background major histocompatibility antigen can effectively diversify the TCR repertoire for a foreign epitope by defecting the response away from an immunodominant combination of TCR-binding residues.