Vergelli M, Hemmer B, Kalbus M, Vogt A B, Ling N, Conlon P, Coligan J E, McFarland H, Martin R
Neuroimmunology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA.
J Immunol. 1997 Apr 15;158(8):3746-52.
In this report, we demonstrate for autoreactive T cell clones that single amino acid modifications of the antigenic ligand can result in not only abrogated, decreased, or unmodified, but also increased, T cell responsiveness (superagonist ligands). We further studied the effects of combinations of multiple substitutions with different effects in single peptides. Experiments with peptides carrying multiple amino acid exchanges revealed that the final outcome of TCR ligation by a given ligand is the integration of negative, neutral, and positive effects of each single residue. In addition, the introduction of superagonist substitutions together with nonconservative modifications of primary and secondary TCR contacts resulted in stimulatory ligands. These findings indicate that: 1) the specificity of a single TCR is highly degenerate; 2) ligands exist for autoreactive T cells that have higher agonist activity than the autoantigen itself; 3) the rules to search for cross-reactive epitopes in autoimmunity should take into account that amino acids at certain positions within an antigenic peptide may exert superagonist activity and compensate for the negative effects of residues at other positions that would otherwise not be tolerated.
在本报告中，我们证明了对于自身反应性T细胞克隆，抗原配体的单个氨基酸修饰不仅可导致T细胞反应性消除、降低或不变，还可导致其增加（超激动剂配体）。我们进一步研究了单肽中具有不同效应的多个取代组合的影响。对携带多个氨基酸交换的肽进行的实验表明，给定配体与TCR结合的最终结果是每个单个残基的负效应、中性效应和正效应的整合。此外，超激动剂取代与TCR一级和二级接触的非保守修饰一起引入可产生刺激性配体。这些发现表明：1）单个TCR的特异性高度简并；2）存在比自身抗原本身具有更高激动剂活性的自身反应性T细胞配体；3）在自身免疫中寻找交叉反应性表位的规则应考虑到抗原肽内某些位置的氨基酸可能发挥超激动剂活性，并补偿其他位置残基的负面影响，否则这些残基是不能被耐受的。
