p18~(INK4C)调控小鼠T细胞的发育及功能

p18INK4C属于细胞周期蛋白激酶抑制剂,其突变或缺失与某些肿瘤的发生密切相关,如T细胞白血病,但目前关于p18调控T细胞发育及功能的研究还鲜有报道,其调控机制仍不明确.本研究利用p18基因敲除(p18KO)小鼠,系统地研究了胸腺中T细胞的早期发育及成熟T细胞的增殖和活化功能,并利用逆转录病毒的方法在Lin?造血干祖细胞上过表达p18,移植4个月后检测其对T细胞的影响.结果表明,p18的缺失对胸腺T细胞的早期发育影响不明显,但随着p18KO小鼠周龄的增加会促进CD4+CD8+双阳性T细胞的数量,此外,p18还通过影响CD3+成熟T细胞的细胞周期进程及IFN-?,GATA3,Tbx21和Foxp3等的表达增强脾脏T细胞的增殖和活化;进一步在造血干祖细胞上过表达p18后会影响T细胞的发育和成熟,进而纠正T细胞在数量上的异常.本研究阐释了p18在T细胞早期发育及后期活化中的调控机制,并证实可通过在干祖细胞水平改变p18的表达进而影响T细胞的分化,这对p18调控T细胞功能异常及参与T细胞白血病的发生提供了新的理论依据和重要的研究价值.

T Cell Development and Function Are Regulated by p18 INK4C

p18 INK4C （p18） belongs to the cyclin-dependent kinase inhibitor family. Its deletion results in T cell leukemia in mice but its roles in normal T cell development and function remain unclear. This study focuses on T cell development in the thymus and activation and proliferation of mature T cells by using the p18 knockout （plSKO） mice in comparison with p18 wild type （p18WT） mice. Our results show that absence of p18 had no overt effects on early T cell development in the thymus whereas there was an increase of CD4＋CD8＋ double positive T cells in the pl8KO mice. As expected, p18 appeared to be a potent inhibitor for T cell proliferation. In addition, elevation of IFN-γ, GATA3, Tbx21 and Foxp3 were associated with T cell activation in p18KO mice. Furthermore, ectopic expression of p18 hematopoietic stem and progenitor cells affected the development and maturation of T cells, and was able to correct the abnormality in the number of plSKO T ceils. In short, our current study demonstrates p18 as an important regulator for late development, activation and proliferation of T cells, thereby providing a basis for further studies of its roles in T cell disorders such as T cell leukemia.