Cell Cycle Inhibition in Systemic Autoimmunity

描述（由申请人提供）： 该项目将集中于确定细胞周期抑制剂p21在正常免疫和自身免疫反应中的作用。细胞周期在决定细胞的命运和分化状态方面起着关键作用。因此，它受到细胞周期蛋白、细胞周期蛋白依赖性激酶（CDK）和CDK抑制剂（CDKI）7等蛋白质复合物的高度调节，而这些蛋白质复合物又通过许多细胞内信号传导途径受到外部刺激的调节。我们发现，高水平的某些CDKI，包括p21，p18和p27存在于活化/记忆（CD 44 hl）表型的CD 4 + T细胞在狼疮倾向的雄性BXSB小鼠。这样的T细胞通常在狼疮中增加，并且我们假设自身抗原反应性T细胞的重复刺激可能导致类似于“复制性衰老”的状态，其中T细胞不再循环，而是抵抗凋亡，积累和转录自身免疫促进促炎细胞因子。为了测试这种可能性，我们产生并检查了p21缺陷的狼疮易感小鼠，并对p27敲除的自身免疫小鼠进行了初步研究。缺乏p21的雄性BXSB小鼠表现出与增强的T和B淋巴细胞凋亡相关的疾病显著减少，并且显著降低了活化/记忆CD 4 + T细胞的积累。对p27缺陷雄性BXSB小鼠的初步研究也显示死亡率降低。为了进一步研究CDKI在自身免疫和正常免疫应答中的作用，提出了四个目标。第一个将确定p21缺陷对另一种遗传上不同的狼疮易感株NZB. NZW-Lbw 5的影响，NZB. NZW-Lbw 5是一种来自NZB和NZW小鼠的间隔特异性同源系。第二个目标是确定T细胞中p21的表达是否对自身免疫的发展至关重要。第三个目标是研究p21缺陷对外源抗原和LCMV感染的免疫应答的影响。最终的目的是确定Fas诱导的细胞凋亡在BXSB-p21 - 7-小鼠中观察到的疾病减轻中的作用。这些研究应该产生重要的新的见解的意义和作用的p21在系统性自身免疫和宿主对外来抗原的反应。

DESCRIPTION (provided by applicant): This project will focus on defining the role of the cell cycle inhibitor, p21, in normal immune and autoimmune responses. The cell cycle plays a critical role in determining the fate and differentiation state of cells. It is therefore highly regulated by complexes of proteins such as cyclin, cyclin-dependent kinases (CDKs) and CDK inhibitors (CDKIs)7 which in turn are regulated by external stimuli through a number of intracellular signaling pathways. We found that high levels of certain CDKIs, including p21, p18 and p27 are present in activated/memory (CD44hl) phenotype CD4+ T cells in lupus-prone male BXSB mice. Such T cells are commonly increased in lupus and we postulated that repeated stimulation of self-antigen-reactive T cells might lead to a state similar to "replicative senescence", where T cells are no longer cycling, but are resistant to apoptosis, accumulate and transcribe autoimmune-promoting pro-inflammatory cytokines. To test this possibility, we generated and examined lupus-prone mice deficient in p21 and have performed preliminary studies of p27 knockout autoimmune mice. Male BXSB mice lacking p21 exhibited marked reduction in disease associated with enhanced apoptosis of T and B lymphocytes and significantly decreased accumulation of activated/memory CD4+ T cells. Initial studies of p27- deficient male BXSB mice also revealed reduced mortality. To further examine the role of CDKIs in autoimmunity and normal immune response four aims are proposed. The first will determine the effect of p21 deficiency on another genetically distinct lupus-prone strain, NZB.NZW-Lbw5, an interval-specific congenic line derived from NZB and NZW mice. The second aim will determine whether expression of p21 in T cells is critical for the development of autoimmunity. The third aim will examine the effect of p21 deficiency on immune responses to a foreign antigen and LCMV infection. The final aim will determine the role of Fas-induced apoptosis in the disease reduction observed in BXSB-p21"7" mice. These studies should yield important new insights into the significance and role of p21 in systemic autoimmunity and in host response to foreign antigens.