Cross-reactive memory T cells for Epstein-Barr virus augment the alloresponse to common human leukocyte antigens: Degenerate recognition of major histocompatibility complex-bound peptide by T cells and its role in alloreactivity
Cross-reactive memory T cells for Epstein-Barr virus augment the alloresponse to common human leukocyte antigens: Degenerate recognition of major histocompatibility complex-bound peptide by T cells and its role in alloreactivity
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DOI：
10.1002/eji.1830270720
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发表时间：
1997-07-01
影响因子：
5.4
通讯作者：
Moss, DJ
中科院分区：
文献类型：
--
作者：
Burrows, SR;Silins, SL;Moss, DJ
在本报告中，细胞毒性T淋巴细胞(CTL)克隆表现出与两种常见的人类白细胞抗原(HLAB14或B35)中的一种作为同种异体抗原的双重特异性，以及与HLAB8结合的EB病毒(EBV)的免疫优势表位(FLRGRAYGL)。这些T细胞克隆型是从几个不相关的HLAB8(+)、EBV暴露的个体中分离出来的，每种不同的交叉反应模式都与一个共同的公共T细胞受体(TCR)相关。在一些个体中，CTL与这些同种异体抗原的交叉反应完全主导了对这个EBV表位的记忆反应。此外，这些对EBV的记忆T细胞可以被重新激活，作为CTL反应的重要组成部分，以应对表达HLAB14或B35的同种异体刺激细胞。这些数据说明了EBV等免疫原性病毒的感染史如何增强对特定同种异体抗原的反应性；这种影响可能是观察到的疱疹病毒感染与移植物排斥反应和移植物抗宿主病之间的临床联系的基础。我们还利用HLAB35同种异体反应性CTL克隆型探索了T细胞与同种异体抗原交叉反应的分子基础。为了阐明可能被这些T细胞交叉识别的多肽的结构特征，我们筛选了病毒表位的单取代类似物进行识别，揭示了主要组织相容性复合体(MHC)结合肽的广泛特异性。根据CTL在每个多肽位置所耐受的特定氨基酸变化，搜索人类蛋白质序列数据库以寻找与HLAB35相关的可能识别序列。四个多肽(MPEATVYGL、IPIAPVYGM、KPSPPYFGL和KPIVVLHGY)被鉴定为当存在于HLAB35而不是B8时对CTL具有强大的激活配体。因此，能够完全激活单个TCR的等量表位是由与HLAB8或B35结合的序列具有最小同源性的多肽形成的。这些数据表明，TCR对退化肽的识别可能在自身MHC限制性T细胞对同种异体抗原的强烈反应中发挥重要作用。
In the present report, cytotoxic T lymphocyte (CTL) clones are described that display dual specificity for one of two common human leukocyte antigens (HLA B14 or B35) as alloantigens, and an immunodominant epitope (FLRGRAYGL) from Epstein-Barr virus (EBV) that binds to HLA B8. These T cell clonotypes were isolated from several unrelated HLA B8(+), EBV-exposed individuals, and each distinct cross-reactivity pattern was associated with a common, public T cell receptor (TCR). In some individuals, CTL cross-reactive with these alloantigens completely dominated the memory response to this EBV epitope. Moreover, these memory T cells to EBV could be reactivated as a significant component of the repertoire of CTL responding to allogeneic stimulator cells expressing either HLA B14 or B35. These data illustrate how a history of infection with an immunogenic virus such as EBV can augment responsiveness to particular alloantigens; such influences may underlie the observed clinical association between herpesvirus infection and both allograft rejection and graft-versus-host disease. We have also explored the molecular basis for T cell cross-reactivity with alloantigens using the HLA B35 allo-reactive CTL clonotype. To elucidate the structural features of peptides that may be cross-recognized by these T cells, monosubstituted analogs of the viral epitope were screened for recognition, revealing broad specificity for major histocompatibility complex (MHC)-bound peptide. Based on the particular amino acid changes tolerated by the CTL at each peptide position, the human protein sequence database was searched for possible sequences that were recognized in association with HLA B35. Four peptides were identified (MPEATVYGL, IPIAPVYGM, KPSPPYFGL, and KPIVVLHGY) that were powerful activating ligands for the CTL when presented on HLA B35 but not B8. Thus, equivalent epitopes, capable of fully activating a single TCR, were formed by peptides with minimal obvious sequence homology bound to either HLA B8 or B35. These data indicate that degenerate peptide recognition by TCR may play an important role in the vigorous response of self-MHC-restricted T cells to alloantigens.