Dissociation of thymic positive and negative selection in transgenic mice expressing major histocompatibility complex class I molecules exclusively on thymic cortical epithelial cells
Dissociation of thymic positive and negative selection in transgenic mice expressing major histocompatibility complex class I molecules exclusively on thymic cortical epithelial cells
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DOI：
10.1182/blood.v97.5.1336
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发表时间：
2001-03-01
期刊：
影响因子：
20.3
通讯作者：
van Meerwijk, JPM
中科院分区：
文献类型：
--
作者：
Capone, M;Romagnoli, P;van Meerwijk, JPM
胸腺对发育中的T淋巴细胞的阳性和阴性选择使我们面临一个悖论：T细胞抗原受体（TCR）-主要组织相容性复合物（MHC）/肽相互作用如何在前一过程中导致允许细胞存活的信号转导，并在后一过程中诱导程序性细胞死亡或称为无反应性的低反应状态？提出的假设之一指出，TCR-MHC/肽相互作用的结果取决于向发育中的胸腺细胞呈递选择性配体的细胞类型。在这里，我们描述了在胸腺中只在皮质上皮细胞上表达MHC I类分子的转基因小鼠中CD 8（+）T淋巴细胞自身耐受性的发展和缺乏。尽管在专职抗原呈递细胞上没有MHC I类表达，但在外周中观察到正常数量的CD 8（+）细胞。在特异性激活后，转基因CD 8（+）T细胞在体外和体内有效地裂解同基因MHC I类+靶点，表明胸腺皮质上皮（与髓上皮和造血来源的抗原呈递细胞相反）不能诱导耐受。因此，胸腺阳性选择和耐受诱导中涉及的抗原呈递细胞的区室化可以（至少部分地）解释阳性/阴性选择悖论。（Blood，2001;97：1336-1342）（C）2001年美国血液学会。
Thymic positive and negative selection of developing T lymphocytes confronts us with a paradox: How can a T-cell antigen receptor (TCR)-major histocompatibility complex (MHC)/peptide interaction in the former process lead to transduction of signals allowing for cell survival and in the latter induce programmed cell death or a hyporesponsive state known as anergy? One of the hypotheses put forward states that the outcome of a TCR-MHC/peptide interaction depends on the cell type presenting the selecting ligand to the developing thymocyte. Here we describe the development and lack of self-tolerance of CD8(+) T lymphocytes in transgenic mice expressing MHC class I molecules in the thymus exclusively on cortical epithelial cells. Despite the absence of MHC class I expression on professional antigen-presenting cells, normal numbers of CD8(+) cells were observed in the periphery. Upon specific activation, transgenic CD8(+) T cells efficiently lysed syngeneic MHC class I+ targets in vitro and in vivo, indicating that thymic cortical epithelium (in contrast to medullary epithelium and antigen-presenting cells of hematopoietic origin) is incapable of tolerance induction. Thus, compartmentalization of the antigen-presenting cells involved in thymic positive selection and tolerance induction can (at least in part) explain the positive/negative selection paradox. (Blood, 2001;97:1336-1342) (C) 2001 by The American Society of Hematology.