von Herrath M G, Dockter J, Nerenberg M, Gairin J E, Oldstone M B
Department of Neuropharmacology, Scripps Research Institute, La Jolla, California 92037.
J Exp Med. 1994 Nov 1;180(5):1901-10. doi: 10.1084/jem.180.5.1901.
Upon primary challenge with lymphocytic choriomeningitis virus (LCMV), H-2d (BALB/cByJ) mice mount a cytotoxic T lymphocyte (CTL) response to a single immunodominant domain of the viral nucleoprotein (NP) but no detectable response to the viral glycoprotein (GP). To manipulate this CTL response, the viral NP gene was expressed in the thymus and peripheral T lymphocytes using the murine Thy1.2 promoter. As a result, such Thy1.2-NP (H-2d) transgenic (tg) mice deleted their high-affinity anti-LCMV-NP CTL, but generated equal numbers of lower-affinity NP CTL. Further, they made an alternative anti-LCMV-GP CTL response that is not normally found in non-tg mice indicating a hierarchial control of the CTL response. Unlike the H-2d mice, H-2b (C57Bl/6J) mice normally mount a CTL response to both LCMV-GP and -NP. When the LCMV-NP was expressed using the Thy1.2 promoter in these H-2b mice, the LCMV-NP-specific CTL response was completely aborted and no CTL to new, alternative viral epitopes were generated. Dilutions of H-2b or H-2d NP peptides indicated that 3-4 logs less H-2b NP peptide was required to sensitize syngeneic target cells for CTL-specific lysis, suggesting that the differing affinities of H-2b and H-2d major histocompatibility complex molecules for their peptides likely account for the total removal of NP CTL in the H-2b mice but only partial removal in H-2d mice made to express thymic NP. Thymic grafting experiments done with thymi from newborn Thy1.2-NP tg mice show that selection processes studied in this model are of central (thymic) origin and are not caused by Thy1.2-positive LCMV-NP-expressing T lymphocytes in the periphery.
在用淋巴细胞性脉络丛脑膜炎病毒（LCMV）进行初次攻击时，H-2d（BALB/cByJ）小鼠对病毒核蛋白（NP）的单个免疫显性结构域产生细胞毒性T淋巴细胞（CTL）反应，但对病毒糖蛋白（GP）没有可检测到的反应。为了操纵这种CTL反应，使用鼠Thy1.2启动子在胸腺和外周T淋巴细胞中表达病毒NP基因。结果，这种Thy1.2-NP（H-2d）转基因（tg）小鼠删除了它们的高亲和力抗LCMV-NP CTL，但产生了数量相等的低亲和力NP CTL。此外，它们产生了非转基因小鼠中通常不存在的替代性抗LCMV-GP CTL反应，表明CTL反应存在层级控制。与H-2d小鼠不同,H-2b（C57Bl/6J）小鼠通常对LCMV-GP和-NP都产生CTL反应。当在这些H-2b小鼠中使用Thy1.2启动子表达LCMV-NP时，LCMV-NP特异性CTL反应完全中止，并且没有产生针对新的替代性病毒表位的CTL。H-2b或H-2d NP肽的稀释表明，使同基因靶细胞对CTL特异性裂解敏感所需的H-2b NP肽少3-4个对数，这表明H-2b和H-2d主要组织相容性复合体分子对其肽的不同亲和力可能解释了H-2b小鼠中NP CTL的完全清除，但在表达胸腺NP的H-2d小鼠中只是部分清除。用新生Thy1.2-NP tg小鼠的胸腺进行的胸腺移植实验表明，在该模型中研究的选择过程起源于中枢（胸腺），而不是由外周表达Thy1.2阳性LCMV-NP的T淋巴细胞引起的。
