The CD8+ T cell repertoire in beta 2-microglobulin-deficient mice is biased towards reactivity against self-major histocompatibility class I.
The CD8+ T cell repertoire in beta 2-microglobulin-deficient mice is biased towards reactivity against self-major histocompatibility class I.
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Beta 2-微球蛋白缺陷型小鼠中的CD8+ T细胞库有偏向于反应性。
DOI：
10.1084/jem.179.2.661
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发表时间：
1994-02-01
影响因子：
15.3
通讯作者：
Karre, K
中科院分区：
文献类型：
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作者：
Glas, R;Ohlen, C;Hoglund, P;Karre, K
据报道，β 2-微球蛋白缺陷型（β 2 m-/-）小鼠缺乏主要组织相容性复合体（MHC）I类分子、CD 8 + T细胞的细胞表面表达，以及产生MHC I类特异性T细胞应答的能力。我们已经观察到，β 2 m-/-小鼠具有CD 8 + T细胞，其可以通过体内引发被诱导以针对非自身MHC I类执行强同种特异性细胞毒性应答。我们报告说，这些β 2 m-/-细胞毒性T淋巴细胞（CTL）不同于那些诱导β 2 m阳性的同窝仔，他们交叉反应，并杀死细胞表达自我MHC I类在正常配体密度与β 2 m。β 2 m-/- CTL甚至可以在原代混合淋巴细胞培养物中由表达自身MHC I类的刺激细胞诱导，而同种异体刺激细胞在类似条件下不能引起应答。细胞表面MHC I类表达降低的细胞敏感性较低，而同基因β 2 m-/-细胞对β 2 m-/- CTL具有抗性。当β 2 m-/- T细胞在骨髓嵌合小鼠中具有正常MHC I类表达的环境中成熟时，不能诱导这种抗自身MHC反应性。还观察到针对表达适当的鼠I类分子的人肽加载缺陷细胞的抗自身- MHC反应性，表明与自身-MHC I类的亲和力可发生而与肽含量无关。结果符合一个模型，其中β 2 m-/-小鼠中CD 8 + T细胞的阳性和阴性选择由低水平的MHC I类游离重链介导。在该模型中，选择细胞时的低配体密度导致结合低水平MHC I类游离重链的稀有T细胞的阳性选择，导致非常小的外周CD 8+隔室。由于选择配体的低密度，阴性选择不会去除识别在正常配体密度下表达自身MHC I类的β 2 m阳性细胞的T细胞，这产生了在β 2 m阳性同窝仔中具有自身反应性的T细胞库。因此，第一个“MHC缺陷”的动物矛盾地提供了一个工具，直接演示和分析自身的MHC偏好的T细胞库。
Beta 2-Microglobulin-deficient (beta 2m -/-) mice are reported to lack cell surface expression of major histocompatibility complex (MHC) class I molecules, CD8+ T cells, and the ability to mount MHC class I- specific T cell responses. We have observed that beta 2m -/- mice possess CD8+ T cells that can be induced to perform strong allospecific cytotoxic responses against nonself-MHC class I by in vivo priming. We report that these beta 2m -/- cytotoxic T lymphocyte (CTL) differ from those induced in beta 2m-positive littermates in that they cross-react and kill cells expressing self-MHC class I at normal ligand density with beta 2m. beta 2m -/- CTL could even be induced in primary mixed lymphocyte culture by self-MHC class I expressing stimulator cells, whereas allogeneic stimulator cells failed to elicit a response under similar conditions. Cells with a reduced cell surface MHC class I expression were less sensitive, while syngeneic beta 2m -/- cells were resistant to the beta 2m -/- CTL. This antiself-MHC reactivity could not be induced when beta 2m -/- T cells matured in an environment with normal MHC class I expression in bone marrow chimeric mice. Antiself- MHC reactivity was also observed against human peptide loading- deficient cells expressing the appropriate murine class I molecules, suggesting that affinity to self-MHC class I may occur irrespective of peptide content. The results fit with a model where positive and negative selection of CD8+ T cells in beta 2m -/- mice is mediated by low levels of MHC class I free heavy chains. In this model, low ligand density on selecting cells leads to positive selection of rare T cells that bind to low levels of MHC class I free heavy chains, resulting in a very small peripheral CD8+ compartment. Due to low density of the selecting ligand, negative selection does not remove T cells recognizing beta 2m-positive cells expressing self-MHC class I at normal ligand density, which generates a T cell repertoire that would be autoreactive in a beta 2m-positive littermate. The first "MHC deficient" animals thus paradoxically provide a tool for direct demonstration and analysis of self MHC bias in the T cell repertoire.