Milich D R, Jones J E, McLachlan A, Houghten R, Thornton G B, Hughes J L
Department of Molecular Biology, Research Institute of Scripps Clinic, La Jolla, CA 92037.
J Immunol. 1989 Nov 15;143(10):3148-56.
One purpose of this study was to examine the concept of T cell immunodominance employing a neonatal tolerance model. The extent to which a single T cell recognition site can represent the total T cell response to hepatitis B core Ag (HBcAg) was examined in the B10.S and B10 murine strains. It was shown that the entire B10.S T cell response to HBcAg was focused on a single immunodominant site represented by residues 120-131. This was demonstrated by exposing B10.S neonatal mice to p120-140 or p120-131, which resulted in a state of T cell tolerance to the entire HBcAg. In contrast, p120-140 contained an immunogenic T cell site for B10 mice, p129-140, but this site was nontolerogenic. Similarly, injection of p120-140 into (B10.S X B10)F1 neonatal mice resulted in tolerization of p120-131-specific, I-As-restricted T cells, but not of p129-140-specific, I-Ab-restricted T cells. The second purpose of this study was to attempt to explain the immunologic basis of an immunogenic yet nontolerogenic T cell determinant. It was shown that the p120-131 T cell site, which is immunogenic and tolerogenic in B10.S mice, could be converted into an immunogenic/nontolerogenic T cell site by a single amino acid substitution in either residue 127 or 129. Residues 127 and 129 were previously shown to be involved in interaction with MHC class II molecules (agretopic). These results demonstrated that the relative avidity of a peptide-MHC interaction can influence T cell tolerance induction. Furthermore, the results suggest that a higher threshold of peptide-MHC avidity may be required to induce T cell tolerance as compared to the threshold of peptide-MHC avidity required to immunize T cells.
本研究的一个目的是利用新生期耐受模型来研究T细胞免疫显性的概念。在B10.S和B10小鼠品系中，检测了单个T细胞识别位点能够代表对乙肝核心抗原（HBcAg）的总T细胞反应的程度。结果显示，B10.S小鼠对HBcAg的整个T细胞反应集中于由120 - 131位氨基酸残基所代表的单个免疫显性位点。通过将B10.S新生小鼠暴露于p120 - 140或p120 - 131可证明这一点，这会导致对整个HBcAg产生T细胞耐受状态。相比之下，p120 - 140包含一个对B10小鼠具有免疫原性的T细胞位点，即p129 - 140，但该位点不具有耐受原性。同样，将p120 - 140注射到（B10.S×B10）F1新生小鼠体内，会导致对p120 - 131特异性的、I - As限制性T细胞产生耐受，但对p129 - 140特异性的、I - Ab限制性T细胞则不会。本研究的第二个目的是试图解释一个具有免疫原性但不具有耐受原性的T细胞决定簇的免疫学基础。结果显示，在B10.S小鼠中具有免疫原性和耐受原性的p120 - 131 T细胞位点，可通过在127位或129位氨基酸残基处进行单个氨基酸替换，转变为具有免疫原性/不具有耐受原性的T细胞位点。先前已表明127位和129位氨基酸残基参与与MHC II类分子的相互作用（抗原结合位）。这些结果表明，肽 - MHC相互作用的相对亲和力可影响T细胞耐受的诱导。此外，结果提示，与激活T细胞所需的肽 - MHC亲和力阈值相比，诱导T细胞耐受可能需要更高的肽 - MHC亲和力阈值。
