Gregori Silvia, Giarratana Nadia, Smiroldo Simona, Adorini Luciano
BioXell, Milan, Italy.
J Immunol. 2003 Oct 15;171(8):4040-7. doi: 10.4049/jimmunol.171.8.4040.
In the nonobese diabetic (NOD) mouse, pathogenic and suppressor CD4(+) T cells can be distinguished by the constitutive expression of CD25. In this study, we demonstrate that the progression of autoimmune diabetes in NOD mice reflects modifications in both T cell subsets. CD4(+)CD25(+) suppressor T cells from 8-, but not 16-wk-old NOD mice delayed the onset of diabetes transferred by 16-wk-old CD25-depleted spleen cells. These results were paralleled by the inhibition of alloantigen-induced proliferation of CD4(+)CD25(-) cells, indicating an age-dependent decrease in suppressive activity. In addition, CD4(+)CD25(-) pathogenic T cells became progressively less sensitive to immunoregulation by CD4(+)CD25(+) T cells during diabetes development. CD4(+)CD25(-) T cells showed a higher proliferation and produced more IFN-gamma, but less IL-4 and IL-10, whereas CD4(+)CD25(+) T suppressor cells produced significantly lower levels of IL-10 in 16- compared with 8-wk-old NOD mice. Consistent with these findings, a higher frequency of Th1 cells was observed in the pancreas of 16-wk-old compared with 8-wk-old NOD mice. An increased percentage of CD4(+)CD25(-) T cells expressing CD54 was present in 16-wk-old and in diabetic NOD, but not in BALB/c mice. Costimulation via CD54 increased the proliferation of CD4(+)CD25(-) T cells from 16-, but not 8-wk-old NOD mice, and blocking CD54 prevented their proliferation, consistent with the role of CD54 in diabetes development. Thus, the pathogenesis of autoimmune diabetes in NOD mice is correlated with both an enhanced pathogenicity of CD4(+)CD25(-) T cells and a decreased suppressive activity of CD4(+)CD25(+) T cells.
在非肥胖糖尿病（NOD）小鼠中，致病性和抑制性CD4(+) T细胞可通过CD25的组成性表达来区分。在本研究中，我们证明NOD小鼠自身免疫性糖尿病的进展反映了两个T细胞亚群的变化。来自8周龄而非16周龄NOD小鼠的CD4(+)CD25(+)抑制性T细胞延迟了由16周龄CD25缺失的脾细胞转移的糖尿病的发病。这些结果与同种异体抗原诱导的CD4(+)CD25(-)细胞增殖受到抑制相平行，表明抑制活性存在年龄依赖性下降。此外，在糖尿病发展过程中，CD4(+)CD25(-)致病性T细胞对CD4(+)CD25(+) T细胞的免疫调节作用变得越来越不敏感。CD4(+)CD25(-) T细胞表现出更高的增殖能力，产生更多的IFN-γ，但产生的IL-4和IL-10较少，而与8周龄NOD小鼠相比，16周龄NOD小鼠中CD4(+)CD25(+) T抑制细胞产生的IL-10水平显著降低。与这些发现一致，与8周龄NOD小鼠相比，16周龄NOD小鼠胰腺中Th1细胞的频率更高。在16周龄和糖尿病NOD小鼠中，表达CD54的CD4(+)CD25(-) T细胞百分比增加，但在BALB/c小鼠中未增加。通过CD54的共刺激增加了16周龄而非8周龄NOD小鼠中CD4(+)CD25(-) T细胞的增殖，而阻断CD54可阻止其增殖，这与CD54在糖尿病发展中的作用一致。因此，NOD小鼠自身免疫性糖尿病的发病机制与CD4(+)CD25(-) T细胞致病性增强和CD4(+)CD25(+) T细胞抑制活性降低均相关。
