Le A X, Bernhard E J, Holterman M J, Strub S, Parham P, Lacy E, Engelhard V H
Department of Surgery, University of Virginia Medical Center, Charlottesville 22908.
J Immunol. 1989 Feb 15;142(4):1366-71.
Previous studies have indicated that the frequency of murine CTL precursors (CTLp) for human class I molecules is one to two orders of magnitude lower than that for murine class I alloantigens, and that this is due to species-specific structural differences between these molecules. Transgenic mice expressing the human class I MHC Ag HLA-A2.1 were used to examine changes in the frequency of class I HLA-specific precursors after T cell differentiation in an HLA-A2.1 positive environment. The HLA-A2.1 gene product was expressed at levels comparable to those of the endogenous H-2Db molecule in thymus, bone marrow, and spleen. By limiting dilution analysis, it was observed that the frequencies of CTLp in transgenic mice responding to the human alloantigens HLA-B7 or HLA-A2.2 were comparable to or lower than those in normal C57BL/6 mice, regardless of whether the Ag was presented on human or murine cells. Thus, expression of a human class I molecule in these animals did not result in an expansion of the number of CTLp specific for other human class I Ag. In addition, the frequency of HLA-A2.1-restricted, influenza specific CTLp was substantially lower than the frequency of H-2b restricted CTLp, indicating a poor utilization of HLA-A2.1 as a restricting element. Finally, the frequencies of CTLp for HLA-A2.1 expressed on syngeneic murine tumor cells were decreased significantly. Thus, expression of HLA-A2.1 in these animals appeared to induced tolerance to this Ag. Interestingly, however, these mice were not tolerant to the HLA-A2.1 molecule expressed on human cells. This indicates that the HLA-A2.1 associated epitopes expressed on murine and human cells differ and suggests that, under these circumstances, HLA-A2.1 acts as a restricting element for human nominal Ag. These results are discussed in the context of current models of T cell repertoire development.
先前的研究表明，针对人类I类分子的小鼠细胞毒性T淋巴细胞前体（CTLp）的频率比针对小鼠I类同种异体抗原的频率低一到两个数量级，这是由于这些分子之间存在物种特异性结构差异。表达人类I类主要组织相容性抗原HLA-A2.1的转基因小鼠被用于检测在HLA-A2.1阳性环境中T细胞分化后I类HLA特异性前体频率的变化。HLA-A2.1基因产物在胸腺、骨髓和脾脏中的表达水平与内源性H-2Db分子相当。通过有限稀释分析观察到，无论抗原是呈递在人类细胞还是小鼠细胞上，转基因小鼠中对人类同种异体抗原HLA-B7或HLA-A2.2产生反应的CTLp频率与正常C57BL/6小鼠中的频率相当或更低。因此，在这些动物中表达人类I类分子并不会导致对其他人类I类抗原具有特异性的CTLp数量增加。此外，HLA-A2.1限制性流感特异性CTLp的频率显著低于H-2b限制性CTLp的频率，表明HLA-A2.1作为限制性元件的利用率较低。最后，在同基因小鼠肿瘤细胞上表达的HLA-A2.1的CTLp频率显著降低。因此，在这些动物中表达HLA-A2.1似乎诱导了对该抗原的耐受性。然而，有趣的是，这些小鼠对人类细胞上表达的HLA-A2.1分子并不耐受。这表明在小鼠和人类细胞上表达的与HLA-A2.1相关的表位不同，并表明在这些情况下，HLA-A2.1作为人类名义抗原的限制性元件。这些结果将在当前T细胞库发育模型的背景下进行讨论。
