Department of Pathobiology, University of Pennsylvania, Philadelphia, PA 19104, USA.
Blood. 2010 Mar 18;115(11):2186-95. doi: 10.1182/blood-2009-08-237438. Epub 2009 Dec 22.
Central and peripheral tolerance is required to prevent immune responses to self-antigens. We now present a mouse model in which wild-type (WT) SH2 domain-containing leukocyte phosphoprotein of 76 kDa (SLP-76) has been constitutively targeted to the membrane, where CD4+ T cells become spontaneously dysregulated and develop an inflammatory phenotype. Mice bearing membrane-targeted SLP-76 (MTS) have a partial T-cell lymphopenia and impaired signaling though the mature T-cell receptor. The CD4+ T cells that develop in these mice possess an activated-like phenotype and are skewed toward the inflammatory T(H)1 and T(H)17 lineages. MTS mice also spontaneously develop autoantibodies at an early age. To rule out abnormal thymic selection as the sole cause of the MTS phenotype, we expressed WT SLP-76 along with the MTS followed by deletion of the WT allele in peripheral T cells. The peripheral MTS-expressing T cells demonstrate skewed cytokine responses when transferred into lymphopenic hosts. Thus, the abnormal effector T-cell phenotype still occurs in the presence of preserved central and peripheral tolerance, suggesting that diminished T-cell receptor signaling can promote skewed T-cell responses.
中央和外周耐受是防止针对自身抗原的免疫反应所必需的。我们现在提出了一种小鼠模型，其中野生型（WT）SH2 结构域包含白细胞磷酸蛋白 76kDa（SLP-76）被持续靶向到膜上，在那里 CD4+T 细胞变得自发失调并发展出炎症表型。携带膜靶向 SLP-76（MTS）的小鼠具有部分 T 细胞淋巴细胞减少症，并通过成熟 T 细胞受体受损信号转导。在这些小鼠中发育的 CD4+T 细胞具有激活样表型，并偏向于炎症性 T(H)1 和 T(H)17 谱系。MTS 小鼠还会在早期自发产生自身抗体。为了排除异常胸腺选择作为 MTS 表型的唯一原因，我们在表达 WT SLP-76 的同时表达 MTS，然后在周围 T 细胞中删除 WT 等位基因。当外周 MTS 表达的 T 细胞转移到淋巴减少的宿主中时，它们表现出偏向的细胞因子反应。因此，即使存在保留的中央和外周耐受，异常效应 T 细胞表型仍然会发生，这表明 T 细胞受体信号的减弱可以促进偏向的 T 细胞反应。
