Gonsky R, Deem R L, Lee D H, Chen A, Targan S R
Inflammatory Bowel Disease Research Center, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
J Immunol. 1999 Jun 1;162(11):6621-9.
The pathways leading to activation in lamina propria (LP) T cells are different from peripheral T cells. LP T cells exhibit enhanced IL-2 secretion when activated through the CD2 pathway. Coligation of CD28 leads to synergistic enhancement of IL-2 secretion. Previous studies have characterized the CD28 augmentation of TCR-mediated signaling in peripheral blood T cells through transcriptional activation of an IL-2 promoter CD28 response element (CD28RE), along with enhanced mRNA stability. This study characterized molecular events involved in CD28 costimulation of IL-2 production in LP mononuclear cells (LPMC). LPMC exhibited increased IL-2 production in response to CD28 costimulation, compared with cells activated through CD2 alone. IL-2 secretion was paralleled by increased expression of IL-2 mRNA, resulting from enhanced IL-2 mRNA stability. In contrast to transcriptional activation in PBMC, EMSA revealed that CD28 coligation of CD2-activated LPMC does not result in increased binding of trans-factors to the CD28RE, nor did Western blots detect changes in I-kappaBalpha or I-kappaBbeta levels following CD28 coligation. Furthermore, CD28 coligation fails to enhance IL-2 promoter-reporter or RE/AP construct expression in CD2-activated LPMC. The results reported herein indicate that the molecular mechanisms involved in CD28 cosignaling and regulation of IL-2 secretion in LP T cells are unique to that compartment and differ from those seen in peripheral blood T cells. These observations suggest a biological significance for different mechanisms of IL-2 activation in initiation and maintenance of the cytokine repertoire found in the mucosa.
固有层（LP）T细胞的激活途径与外周T细胞不同。LP T细胞通过CD2途径激活时，IL-2分泌增强。CD28共刺激可导致IL-2分泌协同增强。先前的研究通过IL-2启动子CD28反应元件（CD28RE）的转录激活以及增强的mRNA稳定性，对外周血T细胞中TCR介导信号传导的CD28增强作用进行了表征。本研究表征了LP固有固有层单核细胞（LPMC）中CD28共刺激IL-2产生所涉及的分子事件。与仅通过CD2激活的细胞相比，LPMC对CD28共刺激的反应是IL-2产生增加。IL-2分泌伴随着IL-2 mRNA表达增加，这是由于IL-2 mRNA稳定性增强所致。与外周血单个核细胞（PBMC）中的转录激活相反，电泳迁移率变动分析（EMSA）显示，CD2激活的LPMC的CD28共刺激不会导致转录因子与CD28RE的结合增加，Western印迹也未检测到CD28共刺激后I-κBα或I-κBβ水平的变化。此外，CD28共刺激未能增强CD2激活的LPMC中IL-2启动子报告基因或RE/AP构建体的表达。本文报道的结果表明，LP T细胞中CD28共信号传导和IL-2分泌调节所涉及的分子机制在该区域是独特的，与外周血T细胞中所见的机制不同。这些观察结果表明，IL-2激活的不同机制在黏膜中细胞因子库的起始和维持中具有生物学意义。
