Department of Microbiology and Immunology, University of California, San Francisco, CA, USA.
Eur J Immunol. 2010 Feb;40(2):539-47. doi: 10.1002/eji.200939645.
The tyrosine kinase Fyn has been implicated as playing an important role in the generation of both stimulatory and inhibitory signaling events induced by TCR engagement. To assess the role of Fyn for antigen-driven negative selection and Treg development, which are both dependent on the strength and nature of TCR signaling, we generated mice that co-express the transgenes for OVA and the OT-II TCR, which recognizes a peptide from OVA. In mice expressing both transgenes, negative selection, Treg development in the thymus, and the number of Treg in the periphery were each unaffected by ablation of Fyn. Moreover, fyn(-/-) Treg were functional, as assessed in vitro. We further tested the role of Fyn for the adaptor function of c-Cbl, using mice containing a point mutation in c-Cbl that abolishes its E3 ubiquitin ligase function but maintains its adaptor function. The functional and signaling properties of this mutant c-Cbl were unaltered in fyn(-/-) thymocytes. Combined, these data indicate that Fyn was not required for the induction of central tolerance by negative selection, the adaptor protein role of c-Cbl, or the normal development and function of Treg.
酪氨酸激酶 Fyn 被认为在 TCR 结合诱导的刺激和抑制信号事件的产生中发挥重要作用。为了评估 Fyn 在抗原驱动的阴性选择和 Treg 发育中的作用，这两者都依赖于 TCR 信号的强度和性质，我们生成了共表达 OVA 和 OT-II TCR 的转基因小鼠，该 TCR 识别 OVA 肽。在表达两种转基因的小鼠中，Fyn 的缺失对阴性选择、胸腺中 Treg 的发育以及外周 Treg 的数量均没有影响。此外，体外评估表明，fyn(-/-)Treg 是有功能的。我们进一步测试了 Fyn 在 c-Cbl 的衔接蛋白功能中的作用，使用含有 c-Cbl 点突变的小鼠，该突变消除了其 E3 泛素连接酶功能，但保留了其衔接蛋白功能。这种突变型 c-Cbl 在 fyn(-/-)胸腺细胞中的功能和信号特性没有改变。综合这些数据表明，Fyn 对于阴性选择诱导的中枢耐受、c-Cbl 的衔接蛋白作用或 Treg 的正常发育和功能不是必需的。
