Retrogenic modeling of experimental allergic encephalomyelitis associates T cell frequency but not TCR functional affinity with pathogenicity.
Retrogenic modeling of experimental allergic encephalomyelitis associates T cell frequency but not TCR functional affinity with pathogenicity.
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实验性过敏性脑脊髓炎的后源建模是T细胞频率，而不是致病性的TCR功能亲和力。
DOI：
10.4049/jimmunol.181.1.136
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发表时间：
2008-07-01
期刊：
影响因子：
--
通讯作者：
Geiger TL
中科院分区：
文献类型：
--
作者：
Alli R;Nguyen P;Geiger TL
自身特异性T细胞的TCR决定其致病性的特性还不清楚。我们开发了TCR逆转录病毒转基因，或逆转录，髓鞘少突胶质细胞糖蛋白（MOG）诱导的EAE模型，比较五个H-2抗体/MOG 35 -55特异性TCR的病理潜力。将TCR克隆并逆转录病毒转导入TCRαβ缺陷型杂交瘤细胞或Rag 1 −/−骨髓祖细胞中。除了TCR序列之外相同的杂交瘤的比较揭示了对同源抗原的不同的响应性或功能确定的亲和力。通过将转导的祖细胞转移到Rag 1 −/−受体中来产生逆转录小鼠。4周内检测到T细胞。植入水平在不同的TCR之间变化很大，并且在个体小鼠之间显示出单独的变异性。T细胞主要是幼稚的，几乎完全是CD 4+和CD 25-。逆转录T细胞对抗原的相对反应与杂交瘤细胞的反应相同。通过主动免疫诱导EAE导致所有表达MOG特异性TCR的小鼠快速和严重的疾病。小鼠还发生了自发性疾病，其发病率随个体受体而变化。有趣的是，自发性疾病的频率和强度与各自TCR的功能亲和力无关。相反，它与植入水平相关，即使在疾病症状发作前几周测量。我们的研究结果表明，使用逆行建模比较TCR在EAE系统的可行性。他们进一步表明，在表达单型TCR的小鼠中，亲和力不是自发性EAE发展的主要决定因素，并且自身反应性T细胞频率具有更大的意义。
The properties of a self-specific T-cell's TCR that determine its pathogenicity are not well understood. We developed TCR retroviral transgenic, or retrogenic, models of myelin oligodendroglial glycoprotein (MOG)-induced EAE to compare the pathologic potential of five H-2 Ab/MOG35-55-specific TCR. The TCR were cloned and retrovirally transduced into either TCRαβ-deficient hybridoma cells or Rag1−/− bone marrow progenitor cells. Comparison of the hybridomas, identical except for TCR sequence, revealed distinct responsiveness, or functionally-determined affinity, for cognate antigen. Retrogenic mice were produced by transfer of transduced progenitor cells into Rag1−/− recipients. T-cells were detected within 4 weeks. Engraftment levels varied considerably among the different TCR, and showed separate variability among individual mice. T cells were predominantly naïve and virtually exclusively CD4+ and CD25−. Relative responses of the retrogenic T-cells to antigen paralleled that of the hybridoma cells. Induction of EAE through active immunization led to rapid and severe disease in all mice expressing MOG-specific TCR. The mice additionally developed spontaneous disease, the incidence of which varied with the individual receptors. Interestingly, spontaneous disease frequency and intensity could not be correlated with the functional affinity of the respective TCR. Instead, it was associated with engraftment level, even when measured weeks prior to the onset of disease symptoms. Our results demonstrate the feasibility of using retrogenic modeling to compare TCR in the EAE system. They further suggest that affinity is not a primary determinant in spontaneous EAE development in mice expressing monotypic TCR, and that autoreactive T-cell frequency is of greater significance.
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影响因子：
32.4
作者：
Moon, James J.;Chu, H. Hamlet;Jenkins, Marc K.
通讯作者：
Jenkins, Marc K.
DOI：
10.1084/jem.153.5.1198
发表时间：
1981-05-01
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Kappler JW;Skidmore B;White J;Marrack P
通讯作者：
Marrack P
DOI：
10.1073/pnas.96.17.9781
发表时间：
1999-08-17
影响因子：
11.1
作者：
Rees, W;Bender, J;Kappler, J
通讯作者：
Kappler, J
影响因子：
4.4
作者：
Hofstetter, HH;Targoni, OS;Lehmann, PV
通讯作者：
Lehmann, PV
影响因子：
32.4
作者：
Malherbe, L;Hausl, C;McHeyzer-Williams, MG
通讯作者：
McHeyzer-Williams, MG