Watanabe Shiho, Ogawa Shuhei, Hara Yasushi, Tanabe Kazunari, Toma Hiroshi, Abe Ryo
Division of Immunobiology, Research Institute for Biological Sciences, Tokyo University of Science, 2669 Yamazaki, Noda, Chiba 278-0022, Japan.
Transpl Immunol. 2006 Apr;15(4):255-63. doi: 10.1016/j.trim.2006.01.002. Epub 2006 Feb 14.
We found that inducible costimulator (ICOS)-deficient spleen cells have a defect in the ability to induce Th2-mediated chronic graft-versus-host disease (GVHD), whereas they were fully capable of inducing Th1-mediated acute GVHD. In contrast, CD28-deficient spleen cells induced neither acute nor chronic GVHD. To define the mechanisms of how these two CD28 family molecules manifest distinct functions in GVHD, the kinetics of their surface expression by donor T cells in two types of GVHD were investigated. It was found that expression of ICOS by donor T cells dramatically up-regulated after adoptive transfer in both acute and chronic GVHD, but in acute GVHD this up-regulation was transient and quickly down-regulated. In contrast, donor T cells in chronic GVHD maintained high levels of ICOS expression throughout the experiment. These results suggested that ICOS-mediated costimulatory signals are predominantly active in Th2-dominant responses. Changing patterns of CD28 expression by donor T cell were identical in both GVHD as they exhibited slight but sustained up-regulation after transfer, suggesting that CD28 provides a costimulatory signal necessary for the initial T cell activation, regardless of whether in Th1 or Th2 responses. These results lead us to propose that the expression levels of costimulatory receptors are critical for determining the polarization of helper T cell function.
我们发现，可诱导共刺激分子（ICOS）缺陷的脾细胞在诱导Th2介导的慢性移植物抗宿主病（GVHD）的能力上存在缺陷，而它们完全能够诱导Th1介导的急性GVHD。相比之下，CD28缺陷的脾细胞既不能诱导急性GVHD，也不能诱导慢性GVHD。为了确定这两种CD28家族分子在GVHD中如何表现出不同功能的机制，我们研究了供体T细胞在两种类型的GVHD中其表面表达的动力学。结果发现，在急性和慢性GVHD中，过继转移后供体T细胞的ICOS表达均显著上调，但在急性GVHD中，这种上调是短暂的，并迅速下调。相比之下，慢性GVHD中的供体T细胞在整个实验过程中维持高水平的ICOS表达。这些结果表明，ICOS介导的共刺激信号主要在以Th2为主导的反应中起作用。在两种GVHD中，供体T细胞CD28表达的变化模式是相同的，因为它们在转移后均表现出轻微但持续的上调，这表明CD28提供了初始T细胞激活所必需的共刺激信号，无论在Th1还是Th2反应中。这些结果使我们提出，共刺激受体的表达水平对于确定辅助性T细胞功能的极化至关重要。
