Department of Microbiology and Immunology, Burns Institute, First Hospital Affiliated to Chinese PLA General Hospital, Beijing, People's Republic of China.
J Interferon Cytokine Res. 2011 Feb;31(2):249-57. doi: 10.1089/jir.2010.0019. Epub 2010 Nov 17.
To investigate the effect of high-mobility group box 1 (HMGB1) protein on the regulatory T cells (Tregs) in vitro and its potential regulating mechanism in mice. Splenic CD4(+)CD25(+) Tregs and CD4(+)CD25(-) T cells were isolated. The time-dependent and dose-dependent responses between HMGB1 stimulation and cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) and forkhead/winged helix transcription factor p3 (Foxp3) expressions were analyzed. The secretion of various cytokines in the cell suspensions and the proliferation of CD4(+)CD25(-) T cells were determined. HMGB1 was found to be able to markedly down-regulate the expressions of CTLA-4 and Foxp3, especially at 72 h group and in 1,000 ng/mL group (both P < 0.01). The expression of Foxp3 mRNA showed a similar tendency as Foxp3 protein (P < 0.05 or P < 0.01). The secretion of interleukin (IL)-10 from Tregs was decreased when the concentration of HMGB1 was increased. The suppressive activity of proliferation of CD4(+)CD25(-) T cells exceeded 90% when the ratio of Tregs to CD4(+)CD25(-) T cells was 1:1; meanwhile, the proliferation of CD4(+)CD25(-) T cells was enhanced when cultured with HMGB1-stimulated Tregs. In the culture of HMGB1-stimulated Tregs, IL-2 and interferon-γ levels were elevated; whereas IL-4 and IL-10 decreased in CD4(+)CD25(-) T cells after the increased concentration of HMGB1 in comparison with unstimulated-Treg group. HMGB1 stimulation can result in markedly down-regulatory expressions of CTLA-4 as well as in Foxp3 expression and secretion of IL-10 from splenic Tregs in mice. HMGB1 appears to be involved in modulating cell-mediated immunity by influencing proliferation of effector T cells, secretion of IL-2, and cell polarization.
探讨高迁移率族蛋白 B1（HMGB1）蛋白对体外调节性 T 细胞（Tregs）的影响及其在小鼠中的潜在调节机制。
分离脾 CD4+CD25+Tregs 和 CD4+CD25-T 细胞。分析 HMGB1 刺激与细胞毒性 T 淋巴细胞相关抗原 4（CTLA-4）和叉头/翼状螺旋转录因子 p3（Foxp3）表达之间的时间和剂量依赖性反应。测定细胞悬液中各种细胞因子的分泌和 CD4+CD25-T 细胞的增殖。
HMGB1 可显著下调 CTLA-4 和 Foxp3 的表达，尤其是在 72 h 组和 1000ng/ml 组（均 P<0.01）。Foxp3 mRNA 的表达也呈现出类似的趋势（P<0.05 或 P<0.01）。当 HMGB1 浓度增加时，Tregs 分泌的白细胞介素（IL）-10 减少。当 Tregs 与 CD4+CD25-T 细胞的比例为 1:1 时，Tregs 对 CD4+CD25-T 细胞增殖的抑制活性超过 90%；同时，当用 HMGB1 刺激的 Tregs 培养时，CD4+CD25-T 细胞的增殖增强。在 HMGB1 刺激的 Tregs 培养中，IL-2 和干扰素-γ水平升高；而在未刺激的 Treg 组中，当 HMGB1 浓度增加时，CD4+CD25-T 细胞中 IL-4 和 IL-10 减少。
HMGB1 刺激可导致小鼠脾 Tregs 中 CTLA-4 表达及 Foxp3 表达和 IL-10 分泌明显下调。HMGB1 可能通过影响效应 T 细胞的增殖、IL-2 的分泌和细胞极化来调节细胞免疫。
