Liu C P, Parker D, Kappler J, Marrack P
Howard Hughes Medical Institute, National Jewish Medical and Research Center, Denver, Colorado 80206, USA.
J Exp Med. 1997 Nov 3;186(9):1441-50. doi: 10.1084/jem.186.9.1441.
In normal mice, major histocompatibility complex (MHC) proteins are bound to many different peptides, derived from the proteins of their host. In the thymus, the diversity of this collection of MHC + peptide ligands allows thymocytes bearing many different T cell receptors (TCRs) to mature by low avidity reactions between the MHC + peptide ligands and the thymocyte TCRs. To investigate this problem, the selection of T cells specific for a well-studied combination of MHC + peptide, IEk + moth cytochrome c 88-103 (MCC), was investigated. Mice were created that expressed IEk bound to a single peptide, either a variant of MCC in which a critical TCR contact residue, 99K, was changed to A, or a variant of a mouse hemoglobin 64-76 (Hb) peptide, 72A. IEk bound to the MCC variant caused the clonal deletion of some T cells specific for the IEk + MCC ligand; nevertheless, it also positively selected many T cells that could react with this ligand. Some of the TCRs on the selected T cells were related to those on cells from normal mice and some were not. IEk bound to the Hb variant, on the other hand, did not select any T cells which could react with IEk + MCC. These results demonstrate that although positive selection is a partially degenerate event, the sequence of the peptide involved in positive selection controls the selected repertoire.
在正常小鼠中，主要组织相容性复合体（MHC）蛋白与许多源自宿主蛋白的不同肽段结合。在胸腺中，这种MHC+肽配体集合的多样性使得带有许多不同T细胞受体（TCR）的胸腺细胞能够通过MHC+肽配体与胸腺细胞TCR之间的低亲和力反应而成熟。为了研究这个问题，对针对一种经过充分研究的MHC+肽组合（IEk+蛾细胞色素c 88-103，即MCC）的T细胞选择进行了研究。构建了表达与单一肽段结合的IEk的小鼠，该肽段要么是MCC的变体，其中关键的TCR接触残基99K被替换为A，要么是小鼠血红蛋白64-76（Hb）肽72A的变体。与MCC变体结合的IEk导致一些针对IEk+MCC配体的T细胞发生克隆性缺失；然而，它也阳性选择了许多能够与该配体反应的T细胞。所选T细胞上的一些TCR与正常小鼠细胞上的TCR相关，而有些则不相关。另一方面，与Hb变体结合的IEk没有选择任何能够与IEk+MCC反应的T细胞。这些结果表明，尽管阳性选择是一个部分简并的事件，但参与阳性选择的肽段序列控制着所选的T细胞库。
