The Max McGee National Center for Juvenile Diabetes and Human Molecular Genetics Center, Medical College of Wisconsin and the Children's Research Institute of the Children's Hospital of Wisconsin, Milwaukee, Wisconsin, United States of America.
PLoS One. 2007 Jan 3;2(1):e146. doi: 10.1371/journal.pone.0000146.
In experimental models, Type 1 diabetes T1D can be prevented by adoptive transfer of CD4+CD25+ (FoxP3+) suppressor or regulatory T cells. Recent studies have found a suppression defect of CD4+CD25+(high) T cells in human disease. In this study we measure apoptosis of CD4+CD25+(high) T cells to see if it could contribute to reduced suppressive activity of these cells.
T-cell apoptosis was evaluated in children and adolescent 35 females/40 males subjects comprising recent-onset and long-standing T1D subjects and their first-degree relatives, who are at variable risk to develop T1D. YOPRO1/7AAD and intracellular staining of the active form of caspase 3 were used to evaluate apoptosis. Isolated CD4+CD25+(high) and CD4+CD25- T cells were co-cultured in a suppression assay to assess the function of the former cells. We found that recent-onset T1D subjects show increased apoptosis of CD4+CD25+(high) T cells when compared to both control and long-standing T1D subjects p<0.0001 for both groups. Subjects at high risk for developing T1D 2-3Ab+ve show a similar trend p<0.02 and p<0.01, respectively. On the contrary, in long-standing T1D and T2D subjects, CD4+CD25+(high) T cell apoptosis is at the same level as in control subjects p = NS. Simultaneous intracellular staining of the active form of caspase 3 and FoxP3 confirmed recent-onset FoxP3+ve CD4+CD25+(high) T cells committed to apoptosis at a higher percentage 15.3+/-2.2 compared to FoxP3+ve CD4+CD25+(high) T cells in control subjects 6.1+/-1.7 p<0.002. Compared to control subjects, both recent-onset T1D and high at-risk subjects had significantly decreased function of CD4+CD25+(high) T cells p = 0.0007 and p = 0.007, respectively.
There is a higher level of ongoing apoptosis in CD4+CD25+(high) T cells in recent-onset T1D subjects and in subjects at high risk for the disease. This high level of CD4+CD25+(high) T-cell apoptosis could be a contributing factor to markedly decreased suppressive potential of these cells in recent-onset T1D subjects.
在实验模型中，1 型糖尿病（T1D）可以通过过继转移 CD4+CD25+（FoxP3+）抑制性或调节性 T 细胞来预防。最近的研究发现，人类疾病中 CD4+CD25+（高）T 细胞存在抑制缺陷。在这项研究中，我们测量了 CD4+CD25+（高）T 细胞的凋亡，以观察其是否会导致这些细胞的抑制活性降低。
在 35 名女性/40 名男性儿童和青少年受试者中评估 T 细胞凋亡，这些受试者包括近期发病和长期发病的 T1D 受试者及其一级亲属，他们处于发生 T1D 的不同风险中。使用 YOPRO1/7AAD 和 caspase 3 的活性形式的细胞内染色来评估凋亡。分离 CD4+CD25+（高）和 CD4+CD25-T 细胞，并在抑制测定中进行共培养，以评估前者的功能。我们发现，与对照组和长期 T1D 受试者相比，近期发病的 T1D 受试者的 CD4+CD25+（高）T 细胞凋亡增加（p<0.0001，两组均有）。具有高风险发展为 T1D 的受试者 2-3Ab+ve 也显示出相似的趋势（p<0.02 和 p<0.01）。相反，在长期 T1D 和 T2D 受试者中，CD4+CD25+（高）T 细胞凋亡水平与对照组相同（p=NS）。FoxP3 的活性形式的细胞内染色的同时证实，与对照组的 FoxP3+ve CD4+CD25+（高）T 细胞相比，近期发病的 FoxP3+ve CD4+CD25+（高）T 细胞凋亡的比例更高，为 15.3+/-2.2%，而对照组为 6.1+/-1.7%（p<0.002）。与对照组相比，近期发病的 T1D 和高风险受试者的 CD4+CD25+（高）T 细胞功能均显著降低（p=0.0007 和 p=0.007）。
近期发病的 T1D 受试者和高风险疾病受试者的 CD4+CD25+（高）T 细胞中存在更高水平的持续凋亡。这种 CD4+CD25+（高）T 细胞凋亡水平的升高可能是导致近期发病的 T1D 受试者这些细胞抑制潜力显著降低的一个因素。
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