Uenishi H, Iwanami N, Yamagishi H, Nakatani T, Kawasaki T, Tamamura H, Fujii N, Kuribayashi K
Department of Biophysics, Graduate School of Science, Kyoto University, Kyoto, Japan.
Microbiol Immunol. 1998;42(7):479-84. doi: 10.1111/j.1348-0421.1998.tb02313.x.
We previously reported a helper T-cell (Th) epitope (peptide i) which corresponded to the sequence ranging from positions 462 to 479 from the N-terminus of the Friend-murine leukemia virus (F-MuLV) envelope protein (env462-479). Homologous sequences exist in both Moloney-murine leukemia (M-MuLV env452-469) and endogenous AKV (AKV env453-470) viruses, which differ from F-MuLV env462-479 in 5 and 7 amino acids, respectively. However, peptide i-specific Th clones did not respond to either of the corresponding exogenous or endogenous peptides. One amino acid substitution in M-MuLV env452-469 (Asn to Tyr at position 465: N465Y) and three amino acids in AKV env453-470 (H460S, A466Y and Y468H) endowed both peptides with the reactivity to one of the Th clones, F5-5, almost to the same degree as peptide i. However, the other Th clones responded differently to each of the modified endogenous peptides substituted by one to three amino acids. The cells responsive to the cross-reactive peptides occupied only a minor portion, if any, of the bulk cultured lymph node cells from peptide i-immune mice, and in particular, no significant response to the modified endogenous peptides was observed in repeated experiments. The exchange of at least 3 residues was necessary for the endogenous peptide to acquire sufficient cross-reactivity to two of the three Th clones. However, it was noticeable that a single substitution of alanine by tyrosine at the dominant T-cell receptor (TCR) contact position of the peptide i(e) generated a weak but significant cross-reactivity to one of the three Th clones in this study. Thus, peptides of endogenous retroviral origin that would be modified by mutational events might become 'non-self' and prime Th cells leading to auto-antibody production and resulting in autoimmune disease.
我们之前报道过一种辅助性T细胞（Th）表位（肽i），它对应于弗瑞德-小鼠白血病病毒（F-MuLV）包膜蛋白（env462-479）N端第462至479位的序列。莫洛尼-小鼠白血病病毒（M-MuLV env452-469）和内源性AKV病毒（AKV env453-470）中都存在同源序列，它们与F-MuLV env462-479分别有5个和7个氨基酸不同。然而，肽i特异性的Th克隆对相应的外源性或内源性肽均无反应。M-MuLV env452-469中的一个氨基酸替换（第465位的天冬酰胺替换为酪氨酸：N465Y）以及AKV env453-470中的三个氨基酸（H460S、A466Y和Y468H）使这两种肽对其中一个Th克隆F5-5具有反应性，其程度几乎与肽i相同。然而，其他Th克隆对被一至三个氨基酸替换的修饰内源性肽的反应各不相同。对交叉反应性肽有反应的细胞在来自肽i免疫小鼠的大量培养淋巴结细胞中仅占一小部分（如果有的话），特别是在重复实验中未观察到对修饰内源性肽有明显反应。内源性肽要获得对三个Th克隆中两个的足够交叉反应性，至少需要交换3个残基。然而，值得注意的是，在本研究中，在肽i(e)的主要T细胞受体（TCR）接触位置将丙氨酸单个替换为酪氨酸会对三个Th克隆中的一个产生微弱但显著的交叉反应性。因此，因突变事件而被修饰的内源性逆转录病毒来源的肽可能会变成“非自身”并激活Th细胞，导致自身抗体产生并引发自身免疫性疾病。
