Burrows S R, Silins S L, Cross S M, Peh C A, Rischmueller M, Burrows J M, Elliott S L, McCluskey J
Queensland Institute of Medical Research, The Bancroft Centre, Brisbane, Australia.
Eur J Immunol. 1997 Jan;27(1):178-82. doi: 10.1002/eji.1830270126.
The memory response to the immunodominant Epstein-Barr virus (EBV) epitope FLRGRAYGL, which associates with HLA B8, is exceptionally restricted, being dominated by cytotoxic T lymphocytes (CTL) with a single, public T cell receptor (TCR). CTL clones that express this receptor fortuitously cross-react with the alloantigen HLA B44. However, of the two major subtypes of this HLA, B4402 and B4403, that differ by a single amino acid, only the former is recognized by these mature CTL clones. Individuals heterozygous for HLA B8 and B4402 use alternative TCR for the EBV determinant since the dominant TCR is potentially self-reactive. We now demonstrate that this clonotype is also essentially absent from the repertoire of CTL directed against the viral epitope in seven from seven unrelated individuals heterozygous for HLA B8 and B4403. Thus immune tolerance of these CTL recognizing HLA B4402 is associated with expression of either B4402 or B*4403. This suggests that tolerance in the human T cell compartment requires a lower threshold of recognition than for effector function, thus providing a buffer zone minimizing the risk of autoimmunity. These data also illustrate the potential for non-restricting HLA molecules to bias dramatically the T cell repertoire used for specific immune responses. Such influences may be the basis of the "protective" effects of certain HLA alleles in susceptibility to autoimmune disorders.
对与HLA B8相关的免疫显性爱泼斯坦-巴尔病毒（EBV）表位FLRGRAYGL的记忆反应异常受限，主要由具有单一公共T细胞受体（TCR）的细胞毒性T淋巴细胞（CTL）主导。表达这种受体的CTL克隆偶然会与同种异体抗原HLA B44发生交叉反应。然而，在这种HLA的两种主要亚型B4402和B4403中，它们仅相差一个氨基酸，只有前者能被这些成熟的CTL克隆识别。HLA B8和B4402杂合的个体针对EBV决定簇使用替代TCR，因为主导的TCR可能具有自身反应性。我们现在证明，在7名HLA B8和B4403杂合的无关个体中，针对病毒表位的CTL库中也基本不存在这种克隆型。因此，这些识别HLA B4402的CTL的免疫耐受与B4402或B*4403的表达有关。这表明人类T细胞区室中的耐受需要比效应功能更低的识别阈值，从而提供一个缓冲区域，将自身免疫风险降至最低。这些数据还说明了非限制性HLA分子极大地影响用于特异性免疫反应的T细胞库的潜力。这种影响可能是某些HLA等位基因在自身免疫性疾病易感性中产生“保护”作用的基础。
