Sturm Andreas, Itoh Jugoh, Jacobberger James W, Fiocchi Claudio
Division of Gastroenterology, Department of Medicine, University Hospitals of Cleveland, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106-4952, USA.
J Clin Invest. 2002 Jun;109(11):1481-92. doi: 10.1172/JCI14967.
To mount an effective immune response, T cells must divide in response to antigen contact. To maintain tolerance, mucosal lamina propria T cells (LPTs) may adapt their cycling to an antigen-rich gut stimulatory environment. Here, we compared the cell cycle kinetics of LPTs and peripheral blood T cells (PBTs) before and after CD3- and CD2-mediated activation. While CD3-activated naive (CD45RA(+)) and memory (CD45RO(+)) PBTs peaked in the S and G2/M phase at 2-3 days, CD3-activated LPTs peaked at 4-6 days. In contrast, CD2 activation induced modest PBT but vigorous LPT cycling. The doubling time of CD3-activated PBTs was 1 day, while that of CD3- or CD2-activated LPTs was 2 days. LPTs failed to upregulate cyclin-dependent kinase 4 and cyclin D3, but Rb phosphorylation and cyclin A and B1 upregulation were induced by CD2 engagement. The extents of clonal expansion in LPT and PBT were comparable, indicating that LPTs' slow replication delays but does not hinder cell division. CD2-activated LPTs displayed a striking upregulation of p53, whose blockade by antisense oligonucleotides accelerated their S phase transit time to that of CD3-activated PBTs. By slowing LPT cycling, p53 may act as a negative regulator of mucosal immunity, promoting immunological tolerance by preventing excessive T cell replication.
为了产生有效的免疫反应，T细胞必须在接触抗原后进行分裂。为维持免疫耐受，黏膜固有层T细胞（LPT）可能会使其细胞周期适应富含抗原的肠道刺激环境。在此，我们比较了CD3和CD2介导激活前后LPT和外周血T细胞（PBT）的细胞周期动力学。CD3激活的初始（CD45RA(+)）和记忆（CD45RO(+)）PBT在2 - 3天时S期和G2/M期达到峰值，而CD3激活的LPT在4 - 6天时达到峰值。相反，CD2激活诱导PBT适度增殖，但LPT增殖活跃。CD3激活的PBT的倍增时间为1天，而CD3或CD2激活的LPT的倍增时间为2天。LPT未能上调细胞周期蛋白依赖性激酶4和细胞周期蛋白D3，但CD2结合可诱导Rb磷酸化以及细胞周期蛋白A和B1上调。LPT和PBT的克隆扩增程度相当，表明LPT的缓慢复制会延迟但不会阻碍细胞分裂。CD2激活的LPT显示p53显著上调，用反义寡核苷酸阻断p53可使其S期过渡时间加快至CD3激活的PBT的水平。通过减缓LPT的细胞周期，p53可能作为黏膜免疫的负调节因子，通过防止T细胞过度复制来促进免疫耐受。
