調節性T細胞在狼瘡小鼠致病機轉中所扮演的角色

Abstract

最近研究顯示調節性T細胞的不正常可能在自體免疫疾病致病過程中扮演重要角色。一群由胸腺產生持續表現CD25分子的CD4+ 細胞具有免疫抑制能力，去除掉這群CD4+CD25+ T細胞將導致器官特異性自體免疫疾病發生。紅斑性狼瘡是一種慢性全身性的自體免疫疾病，特徵為會產生多種對抗核內抗原的自體抗體。到目前為止，調節性T細胞是否參予這個疾病的致病過程並不清楚。為了去探討這個問題，我們測定狼瘡小鼠(NZB/NZW F1) 與正常小鼠(DBA2/NZW F1) CD4+CD25+ T細胞的比例與相關重要基因表現。結果顯示CD4+CD25+ T細胞的比例在年輕狼瘡小鼠體內較正常小鼠低；但到發病晚期，狼瘡小鼠的CD4+CD25+ T細胞逐漸增加，甚至比正常小鼠高。並且在年輕的狼瘡小鼠中，我們可以偵測到核小體特異性T細胞的存在。我們推測在狼瘡小鼠的調節性T細胞與自體反應T細胞數目的不平衡，可能為導致疾病發展的因素之ㄧ。進一歩研究發現，兩種小鼠的CD4+CD25+ T細胞其Foxp3 與TGF-beta基因表現量差不多，但狼瘡小鼠的CD4+CD25+ T細胞與CD4+CD25- T細胞IL-10的表現都較正常小鼠來的高。由體外抑制細胞增生實驗得到，狼瘡小鼠的CD4+CD25+ T細胞仍具有免疫抑制能力。另一方面，我們利用抗CD25抗體去除掉正常小鼠的CD4+CD25+ T細胞，接著用凋亡小體處理過的樹突細胞破壞其免疫耐受性，並偵測體內自體抗體的產生。我們發現去除掉CD4+CD25+ T細胞的小鼠組別會產生較高的抗雙股/單股去氧核醣核酸抗體。這個結果顯示缺乏CD4+CD25+ T細胞的情況下，會使得調節自體抗體產生的機制受到破壞，證明CD4+CD25+ T細胞在自體免疫反應調控上可能扮演著重要的角色。

Recent studies have suggested that the dysfunction of regulatory T cells might play a critical role in the pathogenesis of autoimmune diseases. A subset of thymus-derived CD4+ cells that constitutively express CD25 exhibits immune suppressive activity. Depletion of CD4+CD25+ T cells has been shown to cause organ-specific autoimmune diseases. Systemic lupus erythematosus (SLE) is a chronic, systemic autoimmune disease characterized by the production of antibodies to components of the cell nucleus. At present, it is unknown if regulatory T (Treg) cells are involved in the pathogenesis of SLE. In order to address this question, we assayed the frequency of CD4+CD25+ T cells and measured the related gene expression levels in CD4+CD25+ T cells isolated from both lupus mice (NZB/NZW F1) and normal mice (DBA2/NZW F1). The data showed that the frequency of CD4+CD25+ T cells in young lupus mice was lower than that in normal mice. But in old mice, the frequency of CD4+CD25+ T cells increased and was even higher than that in age matched normal mice. Nucleosome-specific T cells can also be detected in young lupus mice. Therefore, we proposed that the imblalance of regulatory T cells in lupus mice might cause the development of this disease. Furthermore, the Foxp3 and TGF-beta expression of CD4+CD25+ T cells were very similar between both groups of mice. In contrast, the IL-10 expression of CD4+CD25+ T cells isolated from lupus mice was higher than that of normal mice. In in vitro suppression assays, CD4+CD25+ T cells of lupus mice were found to exert suppressive activities as well. Further, we depleted CD4+CD25+ T cells with anti-CD25 antibodies in non-autoimmune mice and broke the tolerance with dendritic cells pulsed with apoptotic cells for the follow up of autoantibody levels. We found that the mice depleted CD4+CD25+ T cells had higher titer of auto-anti-ds/ss DNA antibodies compared with that of control groups. The finding indicated that CD4+CD25+ T cell activities might be involved in the regulating mechanism of autoantibody production. Although more studies are needed, CD4+CD25+ T cells might play a critical role in the regulation of autoimmune response in murine lupus.