THYMIC SELECTION AND THYMIC MAJOR HISTOCOMPATIBILITY COMPLEX CLASS-II EXPRESSION ARE ABNORMAL IN MICE UNDERGOING GRAFT-VERSUS-HOST REACTIONS
THYMIC SELECTION AND THYMIC MAJOR HISTOCOMPATIBILITY COMPLEX CLASS-II EXPRESSION ARE ABNORMAL IN MICE UNDERGOING GRAFT-VERSUS-HOST REACTIONS
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DOI：
10.1084/jem.178.3.805
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发表时间：
1993-09-01
影响因子：
15.3
通讯作者：
LAPP, WS
中科院分区：
文献类型：
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作者：
DESBARATS, J;LAPP, WS
移植物抗宿主反应（GVHR）会导致胸腺上皮和淋巴室受损，从而导致接受 GVHR 的小鼠胸腺细胞的异常成熟和功能。在本报告中，研究了 GVHR 对胸腺 T 细胞受体 (TCR) 表达和使用的影响。通过静脉内转移亲代淋巴细胞，在未辐射的 F1 杂交小鼠中诱导 GVHR。通过三色流式细胞术研究了由 CD4 和 CD8 定义的胸腺细胞亚群上 CD3/TCR 复合物的表达。 CD4+CD8- 成熟胸腺细胞的 CD3/TCR 水平降低，但 CD4-CD8+ 成熟胸腺细胞不降低。 CD4 单阳性胸腺细胞上缺乏 CD3/TCR 上调，但 CD8+ 胸腺细胞上没有上调，表明接受 GVHR 的小鼠胸腺中 II 类主要组织相容性复合物 (MHC) 表达异常。胸腺冷冻切片的免疫荧光染色显示，GVH 反应性小鼠中 MHC II 类表达显着降低。通过确定胸腺中特定 Vbeta TCR 片段使用的发生率来评估 GVHR 诱导的阳性和阴性选择的变化。在正常小鼠中，任何给定 Vbeta 片段的胸腺细胞使用在相同品系和年龄的个体之间高度一致；然而，观察到 GVH 反应性同窝小鼠之间 TCR Vbeta6hi 和 Vbeta8hi 细胞的发生率存在显着差异，表明这些动物的胸腺阳性选择已失调。此外，负选择是有缺陷的。携带内源性超抗原 Mls-1a 的 GVH 反应性小鼠胸腺中表型自身反应性 Vbeta6hi T 细胞的发生率明显高于未治疗的对照组。因此，接受GVHR的小鼠表现出CD4+CD8-胸腺细胞上有缺陷的TCR上调，并且TCR使用的变化反映了异常的胸腺选择，同时MHC II类表达减少。在 GVH 反应性小鼠中观察到的大多数 TCR 表达和 CD4+ 胸腺细胞使用异常与 II 类基因敲除小鼠相似。
The graft-vs.-host reaction (GVHR) results in damage to the epithelial and lymphoid compartments of the thymus and thus in abnormal maturation and function of thymocytes in mice undergoing GVHR. In this report, the effects of GVHR on thymic T cell receptor (TCR) expression and usage have been investigated. GVHR was induced in unirradiated F1 hybrid mice by the intravenous transfer of parental lymphoid cells. Expression of the CD3/TCR complex on thymocyte subsets defined by CD4 and CD8 was studied by three-color flow cytometry. The level of CD3/TCR was decreased on CD4+CD8-, but not CD4-CD8+, mature thymocytes. The lack of upregulation of CD3/TCR on CD4 single-positive thymocytes, but not on their CD8+ counterparts, suggested an abnormality of class II major histocompatibility complex (MHC) expression in the thymuses of mice undergoing GVHR. Immunofluorescence staining of thymic frozen sections revealed that MHC class II expression was dramatically decreased in GVH-reactive mice. GVHR-induced changes in positive and negative selection were evaluated by determining the incidence of specific Vbeta TCR segment usage in the thymus. In normal mice, thymocyte usage of any given Vbeta segment was highly consistent between individuals of the same strain and age; however, a marked divergence in the incidence of TCR Vbeta6hi and Vbeta8hi cells between GVH-reactive littermate mice was observed, suggesting that thymic positive selection had become disregulated in these animals. Furthermore, negative selection was defective; the incidence of phenotypically self-reactive Vbeta6hi T cells was significantly greater in the thymuses of GVH-reactive mice bearing the endogenous superantigen Mls-1a than in untreated controls. Thus, mice undergoing GVHR showed defective TCR upregulation on CD4+CD8- thymocytes and changes in TCR usage reflecting aberrant thymic selection, in conjunction with decreased expression of MHC class II. Most abnormalities of TCR expression and usage on CD4+ thymocytes observed in GVH-reactive mice were analogous to those of class II knockout mice.