Priatel John J, Teh Soo-Jeet, Dower Nancy A, Stone James C, Teh Hung-Sia
Department of Microbiology and Immunology, University of British Columbia, Vancouver V6T 1Z3, Canada.
Immunity. 2002 Nov;17(5):617-27. doi: 10.1016/s1074-7613(02)00451-x.
Two important Ras-guanyl nucleotide exchange factors, Sos and RasGRP1, control Ras activation in thymocytes. However, the relative contribution of these two exchange factors to Ras/ERK activation and their resulting impact on positive and negative selection is unclear. We have produced two lines of RasGRP1(-/-) TCR transgenic mice to determine the effect of RasGRP1 in T cell development under conditions of defined TCR signaling. Our results demonstrate that RasGRP1 is crucial for thymocytes expressing weakly selecting TCRs whereas those that express stronger selecting TCRs are more effective at utilizing RasGRP1-independent mechanisms for ERK activation and positive selection. Analysis of RasGRP1(-/-) peripheral T cells also revealed hitherto unidentified functions of RasGRP1 in regulating T cell homeostasis and sustaining antigen-induced developmental programming.
两种重要的Ras鸟苷酸交换因子Sos和RasGRP1控制胸腺细胞中的Ras激活。然而，这两种交换因子对Ras/ERK激活的相对贡献以及它们对阳性和阴性选择的最终影响尚不清楚。我们培育了两系RasGRP1(-/-)TCR转基因小鼠，以确定在明确的TCR信号传导条件下RasGRP1在T细胞发育中的作用。我们的结果表明，RasGRP1对于表达弱选择TCR的胸腺细胞至关重要，而那些表达更强选择TCR的胸腺细胞在利用不依赖RasGRP1的机制进行ERK激活和阳性选择方面更有效。对RasGRP1(-/-)外周T细胞的分析还揭示了RasGRP1在调节T细胞稳态和维持抗原诱导的发育编程方面迄今未被发现的功能。
