Buckley Monica W, Trampont Paul C, Arandjelovic Sanja, Fond Aaron M, Juncadella Ignacio J, Ravichandran Kodi S
Department of Microbiology, Immunology, and Cancer Biology, University of Virginia, Charlottesville, VA 22908; Carter Immunology Center, University of Virginia, Charlottesville, VA 22908; and Center for Cell Clearance, University of Virginia, Charlottesville, VA 22908.
Department of Microbiology, Immunology, and Cancer Biology, University of Virginia, Charlottesville, VA 22908; Carter Immunology Center, University of Virginia, Charlottesville, VA 22908; and Center for Cell Clearance, University of Virginia, Charlottesville, VA 22908
J Immunol. 2015 Feb 15;194(4):1665-76. doi: 10.4049/jimmunol.1401728. Epub 2015 Jan 16.
T cell development in the thymus is a highly regulated process that critically depends upon productive signaling via the preTCR at the β-selection stage, as well as via the TCR for selection from the CD4(+)CD8(+) double-positive stage to the CD4 or CD8 single-positive stage. ShcA is an adapter protein expressed in thymocytes, and it is required for productive signaling through the preTCR, with impaired signaling via ShcA leading to a developmental block at the β-selection checkpoint. However, the role of ShcA in subsequent stages of T cell development has not been addressed. In this study, we generated transgenic mice (CD4-Cre/ShcFFF mice) that specifically express a phosphorylation-defective dominant-negative ShcA mutant (ShcFFF) in late T cell development. Thymocytes in CD4-Cre/ShcFFF mice progressed normally through the β-selection checkpoint, but displayed a significant reduction in the numbers of single-positive CD4(+) and CD8(+) thymocytes. Furthermore, CD4-Cre/ShcFFF mice, when bred with transgenic TCR mouse strains, had impaired signaling through the transgenic TCRs. Consistent with defective progression to the single-positive stage, CD4-Cre/ShcFFF mice also had significant peripheral lymphopenia. Moreover, these CD4-Cre/ShcFFF mice develop attenuated disease in CD4(+) T cell-dependent experimental autoimmune encephalomyelitis, a mouse model of multiple sclerosis. Collectively, these data identify an important role for the adapter protein ShcA in later stages of thymic T cell development and in peripheral T cell-dependent events.
胸腺中的T细胞发育是一个高度受调控的过程，在β选择阶段，它严重依赖通过前T细胞受体（preTCR）的有效信号传导，以及在从CD4(+)CD8(+)双阳性阶段到CD4或CD8单阳性阶段的选择过程中依赖通过T细胞受体（TCR）的信号传导。ShcA是一种在胸腺细胞中表达的衔接蛋白，通过preTCR进行有效信号传导需要它，通过ShcA的信号传导受损会导致在β选择检查点出现发育阻滞。然而，ShcA在T细胞发育后续阶段中的作用尚未得到研究。在本研究中，我们构建了转基因小鼠（CD4-Cre/ShcFFF小鼠），其在T细胞发育后期特异性表达一种磷酸化缺陷的显性负性ShcA突变体（ShcFFF）。CD4-Cre/ShcFFF小鼠的胸腺细胞正常通过β选择检查点，但单阳性CD4(+)和CD8(+)胸腺细胞数量显著减少。此外，CD4-Cre/ShcFFF小鼠与转基因TCR小鼠品系杂交时，通过转基因TCR的信号传导受损。与向单阳性阶段进展存在缺陷一致，CD4-Cre/ShcFFF小鼠外周血淋巴细胞也显著减少。此外，这些CD4-Cre/ShcFFF小鼠在CD4(+)T细胞依赖性实验性自身免疫性脑脊髓炎（一种多发性硬化症的小鼠模型）中疾病症状减轻。总体而言，这些数据表明衔接蛋白ShcA在胸腺T细胞发育后期以及外周T细胞依赖性事件中发挥重要作用。
