AW Morrow Gastroenterology and Liver Centre, Centenary Institute, Royal Prince Alfred Hospital and University of Sydney, Camperdown, NSW 2050, Australia.
J Hepatol. 2012 Oct;57(4):830-6. doi: 10.1016/j.jhep.2012.05.015. Epub 2012 Jun 1.
BACKGROUND & AIMS: The occurrence of primary CD8 T cell activation within the liver, unique among the non-lymphoid organs, is now well accepted. However, the outcome of intrahepatic T cell activation remains controversial. We have previously reported that activation initiated by hepatocytes results in a tolerogenic phenotype characterized by low expression of CD25 and IL-2, poor cytotoxic T lymphocyte (CTL) function, and excessive expression of the pro-apoptotic protein Bim.
To investigate whether this phenotype was due to activation in the absence of co-stimulation, we generated bone marrow (bm) radiation chimeras in which adoptively transferred naïve transgenic CD8 T cells were activated in the presence of co-stimulation by liver bm-derived cells.
Despite expressing pro-inflammatory cytokines, high levels of CD25 and CD54, donor T cells activated by liver bm-derived cells did not produce detectable IL-2 and displayed poor CTL function, suggesting incomplete acquisition of effector function. Simultaneously, these cells expressed high levels of Bim and died by neglect. Transfer of Bim-deficient T cells resulted in increased T cell numbers.
These results imply that expression of CD25 and CD54 is co-stimulation dependent and distinguishes T cell activated by hepatocytes and liver bm-derived cells. In contrast, low expression of IL-2, poor CTL function and excess Bim production represent a more universal phenotype defining T cells undergoing primary activation by both types of hepatic antigen presenting cells (APC). These results have important implications for transplantation, in which all liver antigen presenting cells contribute to activation of T cells specific for the allograft.
肝内初始 CD8 T 细胞的激活（在非淋巴器官中是独特的）现在已被广泛接受。然而，肝内 T 细胞激活的结果仍存在争议。我们之前报道过，由肝细胞引发的激活会导致耐受表型，其特征是 CD25 和 IL-2 的表达水平低、细胞毒性 T 淋巴细胞（CTL）功能差，以及促凋亡蛋白 Bim 的过度表达。
为了研究这种表型是否是由于缺乏共刺激而导致的，我们生成了骨髓（bm）辐射嵌合体，其中通过肝 bm 来源细胞的共刺激，过继转移的幼稚转基因 CD8 T 细胞被激活。
尽管表达了促炎细胞因子、高水平的 CD25 和 CD54，但由肝 bm 来源细胞激活的供体 T 细胞未产生可检测到的 IL-2，且 CTL 功能差，表明效应功能不完全获得。同时，这些细胞表达高水平的 Bim 并因忽视而死亡。转导 Bim 缺陷型 T 细胞会导致 T 细胞数量增加。
这些结果表明 CD25 和 CD54 的表达依赖于共刺激，并区分了由肝细胞和肝 bm 来源细胞激活的 T 细胞。相比之下，低水平的 IL-2、较差的 CTL 功能和过多的 Bim 产生代表了更普遍的表型，定义了由这两种类型的肝抗原提呈细胞（APC）引发的初始激活的 T 细胞。这些结果对移植具有重要意义，因为所有肝抗原提呈细胞都有助于针对同种异体移植物的 T 细胞的激活。
