Glas R, Ohlén C, Höglund P, Kärre K
Microbiology and Tumor Biology Center, Karolinska Institutet, Stockholm, Sweden.
J Exp Med. 1994 Feb 1;179(2):661-72. doi: 10.1084/jem.179.2.661.
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.
据报道，β2微球蛋白缺陷（β2m -/-）小鼠缺乏主要组织相容性复合体（MHC）I类分子的细胞表面表达、CD8 + T细胞以及产生MHC I类特异性T细胞应答的能力。我们观察到，β2m -/-小鼠拥有CD8 + T细胞，通过体内启动可诱导其对非自身MHC I类产生强烈的同种特异性细胞毒性应答。我们报告称，这些β2m -/-细胞毒性T淋巴细胞（CTL）与在β2m阳性同窝小鼠中诱导产生的CTL不同，因为它们会发生交叉反应并杀死表达正常配体密度的自身MHC I类与β2m的细胞。β2m -/- CTL甚至可在原代混合淋巴细胞培养中由表达自身MHC I类的刺激细胞诱导产生，而异基因刺激细胞在类似条件下未能引发应答。细胞表面MHC I类表达降低的细胞敏感性较低，而同基因β2m -/-细胞对β2m -/- CTL具有抗性。当β2m -/- T细胞在骨髓嵌合小鼠中于具有正常MHC I类表达的环境中成熟时，这种抗自身MHC反应性无法被诱导。针对表达适当鼠类I类分子的人肽负载缺陷细胞也观察到了抗自身MHC反应性，这表明对自身MHC I类的亲和力可能与肽含量无关。这些结果符合一个模型，即β2m -/-小鼠中CD8 + 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。在这个模型中，选择细胞上的低配体密度导致对低水平MHC I类游离重链有结合能力的罕见T细胞的阳性选择，从而导致外周CD8 +区室非常小。由于选择配体的低密度，阴性选择不会清除识别以正常配体密度表达自身MHC I类的β2m阳性细胞的T细胞，这就产生了在β2m阳性同窝小鼠中具有自身反应性的T细胞库。因此，第一批“MHC缺陷”动物反常地为直接证明和分析T细胞库中的自身MHC偏向提供了一种工具。
