STRONG XENOGENEIC HLA RESPONSE IN TRANSGENIC MICE AFTER INTRODUCING AN ALPHA-3 DOMAIN INTO HLA-B27
STRONG XENOGENEIC HLA RESPONSE IN TRANSGENIC MICE AFTER INTRODUCING AN ALPHA-3 DOMAIN INTO HLA-B27
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DOI：
10.1038/348642a0
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发表时间：
1990-12-13
期刊：
影响因子：
64.8
通讯作者：
HAMMERLING, GJ
中科院分区：
文献类型：
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作者：
KALINKE, U;ARNOLD, B;HAMMERLING, GJ
小鼠T细胞对同种主要组织相容性复合体（MHC）I类抗原的显著应答的特征是应答细胞的比例相对较大（综述见参考文献1）。然而，其他物种对MHC I类等位基因的反应通常要弱得多2 -5。T淋巴细胞在胸腺MHC抗原上被阳性选择，导致具有强同种异体反应性的T细胞库6。这已经用小鼠T细胞库来解释，由于小鼠中不存在HLA，因此不能有效地选择用于识别HLA分子的小鼠T细胞库。在这里，我们表明，小鼠转基因HLA安装T细胞反应对同种异体HLA是没有比正常小鼠更好。相反，我们决定测试细胞毒性T淋巴细胞上的小鼠辅助分子Lyt-2是否可以与HLA的α3结构域有效地相互作用。为了做到这一点，我们在用于产生转基因小鼠的基因构建体中用鼠α3结构域替换HLA-B27的α3结构域，然后使用这些小鼠的脾细胞刺激正常小鼠T细胞。在这些条件下，产生的细胞毒性T淋巴细胞对异种HLA-B27决定簇的同种异体小鼠I类抗原相同的频率。这些发现表明，通常较弱的异种MHC应答是由于鼠Lyt-2辅助分子与HLA I类的低效相互作用，而不是小鼠T细胞库的限制。
THE pronounced response by mouse T cells to the major histocom-patibility complex (MHC) class I antigens of the same species is characterized by a relatively large fraction of responding cells (reviewed in ref. 1). Responses to MHC class I allelles of other species are, however, generally much weaker2–5. T lymphocytes are positively selected on thymic MHC antigens, resulting in a T-cell repertoire with strong alloreactivity6. This has been explained in terms of a mouse T-cell repertoire that is not efficiently selected for recognition of HLA molecules owing to the absence of HLA in mice. Here we show that mice transgenic for HLA mount a T-cell response against allogeneic HLA that is no better than in normal mice. We decided instead to test whether the mouse accessory molecule Lyt-2 on cytotoxic T lymphocytes could interact efficiently with the α3 domain of HLA. To do this, we replaced the α3 domain of HLA-B27 by a murine α3 domain in a gene construct used to produce transgenic mice, and then used the spleen cells from these mice to stimulate normal mouse T cells. Under these conditions cytotoxic T lymphocytes were generated with the same frequency against xenogeneic HLA-B27 determinants as against allogeneic mouse class I antigens. These findings indicate that the normally weak xeno-MHC response is due to the inefficient interaction of the murine Lyt-2 accessory molecule with HLA class I, and not to limitations of the mouse T-cell repertoire.