Background. 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. Methods and Findings. 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). Conclusions. 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. © 2007 Glisic-Milosavljevic et al.
CITATION STYLE
Glisic-Milosavljevic, S., Waukau, J., Jailwala, P., Jana, S., Khoo, H. J., Albertz, H., … Ghosh, S. (2007). At-risk and recent-onset type 1 diabetic subjects have increased apoptosis in the CD4+CD25+high T-cell fraction. PLoS ONE, 2(1). https://doi.org/10.1371/journal.pone.0000146
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