Department of Immunology, Duke University Medical Center, Durham, NC 27710, USA.
J Immunol. 2012 Oct 15;189(8):4005-13. doi: 10.4049/jimmunol.1201380. Epub 2012 Sep 14.
The ability of the transmembrane adaptor protein linker for activation of T cells (LAT) to regulate T cell development, activation, survival, and homeostasis depends upon phosphorylation of its multiple tyrosine residues. The mutation of tyrosine 136 on LAT abrogates its interaction with phospholipase C-γ1, causing severe ramifications on TCR-mediated signaling. Mice harboring this mutation, LATY136F mice, have significantly impaired thymocyte development; however, they rapidly develop a fatal lymphoproliferative disease marked by the uncontrolled expansion of Th2-skewed CD4(+) T cells, high levels of IgE and IgG1, and autoantibody production. In this study, we assessed the contribution of multiple signaling pathways in LATY136F disease development. The deletion of the critical signaling proteins Gads and RasGRP1 caused a further block in thymocyte development, but, over time, could not prevent CD4(+) T cell hyperproliferation. Also, restoring signaling through the NF-κB and NFAT pathways was unable to halt the development of disease. However, expression of a constitutively active Raf transgene enhanced lymphoproliferation, indicating a role for the Ras-MAPK pathway in LAT-mediated disease.
跨膜衔接蛋白激活 T 细胞（LAT）的能力可以调节 T 细胞的发育、激活、存活和稳态，这依赖于其多个酪氨酸残基的磷酸化。LAT 上酪氨酸 136 的突变使其与磷脂酶 C-γ1 的相互作用丧失，导致 TCR 介导的信号转导严重受损。携带这种突变的 LATY136F 小鼠的胸腺细胞发育明显受损；然而，它们会迅速发展为致命的淋巴增殖性疾病，其特征是 Th2 偏向性 CD4(+) T 细胞的不受控制的扩张、高 IgE 和 IgG1 水平以及自身抗体的产生。在这项研究中，我们评估了多个信号通路在 LATY136F 疾病发展中的作用。关键信号蛋白 Gads 和 RasGRP1 的缺失导致胸腺细胞发育进一步受阻，但随着时间的推移，无法阻止 CD4(+)T 细胞的过度增殖。此外，通过 NF-κB 和 NFAT 途径恢复信号也无法阻止疾病的发展。然而，表达组成性激活的 Raf 转基因增强了淋巴增殖，表明 Ras-MAPK 途径在 LAT 介导的疾病中起作用。
