The T cell response of HLA-DR transgenic mice to human myelin basic protein and other antigens in the presence and absence of human CD4.
The T cell response of HLA-DR transgenic mice to human myelin basic protein and other antigens in the presence and absence of human CD4.
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DOI：
10.1084/jem.181.3.867
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发表时间：
1995-03-01
期刊：
影响因子：
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通讯作者：
Elliott JI
中科院分区：
文献类型：
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作者：
Altmann DM;Douek DC;Frater AJ;Hetherington CM;Inoko H;Elliott JI
近年来，HLA II类转基因小鼠的分析已经从分析具有混合小鼠/人异源二聚体表达的单链HLA II类转基因发展到分析表达正常人异源二聚体的双转基因小鼠。先前的研究使用了HLA转基因小鼠，其中存在与CD 4的物种匹配的相互作用，或缺乏这种相互作用的小鼠。由于据报道这两种系统都能产生HLA限制性反应，因此对物种匹配的CD 4的要求仍不清楚。我们已经产生了三重转基因小鼠表达三种人类转基因，CD 4，DRB，和CD 4，并比较HLA限制性反应之间的肽人类-CD 4+（Hu-CD 4+）和Hu-CD 4-同窝出生。我们没有看到Hu-CD 4+和Hu-CD 4-组之间的差异，这支持了这样的观点，即对于某些应答，至少对物种匹配的CD 4的要求可能不是绝对的。HLA-DR转基因小鼠中小鼠T细胞受体阳性选择的证据来自于对各种肽的新的HLA限制性应答的获得以及使用TCR V β 4基因片段的T细胞频率增加。HLA转基因小鼠功能分析的一个重要目标是阐明人类自身免疫性疾病中自身抗原识别的机制。作为在HLA转基因小鼠中建立“人源化”疾病模型的第一步，我们分析了HLA-DR转基因小鼠对人MPB 139-154肽的反应，该肽被认为是多发性硬化症患者T细胞识别的表位。我们在转基因小鼠中获得了对该表位的T细胞应答，但在非转基因对照中没有。这项研究表明，HLA转基因小鼠将是有价值的HLA限制性T细胞表位的分析与人类疾病，并可能在新的疾病模型的设计。
Analysis of HLA class II transgenic mice has progressed in recent years from analysis of single chain HLA class II transgenes with expression of mixed mouse/human heterodimers to double transgenic mice expressing normal human heterodimers. Previous studies have used either HLA transgenic mice in which there is a species-matched interaction with CD4 or mice which lack this interaction. Since both systems are reported to generate HLA-restricted responses, the matter of the requirement for species-matched CD4 remains unclear. We have generated triple transgenic mice expressing three human transgenes, DRA, DRB, and CD4, and compared HLA-restricted responses to peptide between human- CD4+ (Hu-CD4+) and Hu-CD4- littermates. We saw no difference between Hu- CD4+ and Hu-CD4- groups, supporting the notion that for some responses at least the requirement for species-matched CD4 may not be absolute. Evidence for positive selection of mouse T cell receptors in HLA-DR transgenic mice came both from the acquisition of new, HLA-restricted responses to various peptides and from an increased frequency of T cells using the TCR V beta 4 gene segment. An important goal with respect to the analysis of function in HLA transgenic mice is the clarification of mechanisms which underpin the recognition of self- antigens in human autoimmune disease. As a first step towards 'humanized' disease models in HLA transgenic mice, we analyzed the responses of HLA-DR transgenic mice to the human MPB 139-154 peptide which has been implicated as an epitope recognized by T cells of multiple sclerosis patients. We obtained T cell responses to this epitope in transgenic mice but not in nontransgenic controls. This study suggests that HLA transgenic mice will be valuable in the analysis of HLA-restricted T cell epitopes implicated in human disease and possibly in the design of new disease models.