Threlkeld S C, Wentworth P A, Kalams S A, Wilkes B M, Ruhl D J, Keogh E, Sidney J, Southwood S, Walker B D, Sette A
Department of Immunology, Cytel Corporation, San Diego, CA 92121, USA.
J Immunol. 1997 Aug 15;159(4):1648-57.
Recent data demonstrate that HLA class I alleles can be grouped into superfamilies based on similarities of their peptide-binding motifs. In this study, we have tested the immunogenicity and antigenicity of peptides capable of degenerate binding to multiple HLA class I molecules of the A3-like superfamily. The assay systems utilized included both primary in vitro cultures of lymphocytes from healthy donors, as well as in vitro restimulation of lymphocytes from HIV-infected individuals. Several of the peptides capable of binding more than one HLA A3-like class I molecule were also found to be immunogenic in the context of this same group of A3-like molecules (degenerate CTL recognition). Furthermore, some of the CTL lines thus generated demonstrated promiscuous recognition of the cognate epitope in the context of MHC molecules from more than one member of the superfamily. The fine Ag specificity of this phenomenon was further analyzed using two promiscuous CTL clones derived from A3 and A11 individuals, respectively, and specific for an epitope in the HIV-1 reverse transcriptase. By the use of single-amino acid-substitution analogues, it was demonstrated that the fine specificity of the TCR is largely maintained between MHC-matched and MHC-mismatched presentation of peptide within the A3-like superfamily. These results indicate that the similar peptide-binding specificities among different members of the A3-like superfamily can be reflected in a remarkable similarity in the peptide-MHC complex structures engaged by the TCR and responsible for T cell activation.
近期数据表明，基于肽结合基序的相似性，HLA I类等位基因可被归为超家族。在本研究中，我们测试了能够与A3样超家族的多种HLA I类分子进行简并结合的肽的免疫原性和抗原性。所使用的检测系统包括健康供体淋巴细胞的原代体外培养，以及HIV感染个体淋巴细胞的体外再刺激。在同一组A3样分子的背景下，还发现了几种能够结合不止一种HLA A3样I类分子的肽具有免疫原性（简并CTL识别）。此外，由此产生的一些CTL系在超家族中不止一个成员的MHC分子背景下表现出对同源表位的混杂识别。使用分别来自A3和A11个体、对HIV-1逆转录酶中的一个表位具有特异性的两个混杂CTL克隆，进一步分析了这一现象的精细抗原特异性。通过使用单氨基酸取代类似物，证明了在A3样超家族内，肽在MHC匹配和MHC不匹配呈递之间，TCR的精细特异性在很大程度上得以保持。这些结果表明，A3样超家族不同成员之间相似的肽结合特异性可反映在由TCR参与并负责T细胞激活的肽-MHC复合物结构的显著相似性上。
