Department of Microbiology and Immunology, Burns Institute, First Hospital Affiliated to the Chinese PLA General Hospital, Beijing 100048, People's Republic of China.
Cytokine. 2011 Jun;54(3):296-304. doi: 10.1016/j.cyto.2011.02.017. Epub 2011 Mar 17.
High mobility group box-1 protein (HMGB1), a recently recognized mediator of immune response might contribute to immune suppression when released extracellularly. The present study was performed to clarify effects of HMGB1 on regulatory T cells (Tregs) and the involvement of toll-like receptor (TLR) 4 signaling.
CD4(+)CD25(+)Tregs, isolated from spleens of normal mice and treated with HMGB1 in vitro, and those isolated from HMGB1-treated C3H/HeN (wild type) or C3H/HeJ (TLR4 mutant type) mice, were analyzed for expressions of cytotoxic T lymphocyte-associated antigen (CTLA)4, forkhead/winged helix transcription factor p3 (Foxp3) and interleukin (IL)-10 secretion.
HMGB1-treatment was found to markedly decrease the expressions of CTLA4 and Foxp3, as well as IL-10 secretion. Administration of TLR4 neutralizing antibody abolished the phenotypic and functional changes in Tregs induced by HMGB1. Tregs from HMGB1-treated normal mice showed lower expression of CTLA4, Foxp3, and IL-10 secretion when compared with non-treated mice. Yet opposite results were observed in that of C3H/HeJ mice. Moreover, HMGB1 stimulation could down-regulate the expression of TLR4 on Tregs.
Our data suggest that HMGB1 has the ability to directly modulate the suppressive capacity of CD4(+)CD25(+)Tregs, and TLR4 might be a potential receptor essential for the negative effect of HMGB1 on CD4(+)CD25(+)Tregs activity.
高迁移率族蛋白 B1（HMGB1）是一种新发现的免疫反应介质，当其释放到细胞外时可能会导致免疫抑制。本研究旨在阐明 HMGB1 对调节性 T 细胞（Tregs）的作用及其是否涉及 Toll 样受体（TLR）4 信号通路。
从正常小鼠脾脏中分离出 CD4+CD25+Tregs，并用 HMGB1 体外处理，然后从 HMGB1 处理的 C3H/HeN（野生型）或 C3H/HeJ（TLR4 突变型）小鼠中分离出 Tregs，分析其细胞毒性 T 淋巴细胞相关抗原（CTLA）4、叉头/翅膀螺旋转录因子 p3（Foxp3）和白细胞介素（IL）-10 的表达。
HMGB1 处理明显降低了 CTLA4 和 Foxp3 的表达以及 IL-10 的分泌。TLR4 中和抗体的给药消除了 HMGB1 诱导的 Tregs 表型和功能变化。与未处理的小鼠相比，HMGB1 处理的正常小鼠来源的 Tregs 中 CTLA4、Foxp3 和 IL-10 的表达较低。然而，在 C3H/HeJ 小鼠中观察到相反的结果。此外，HMGB1 刺激可下调 Tregs 上 TLR4 的表达。
我们的数据表明，HMGB1 具有直接调节 CD4+CD25+Tregs 抑制能力的能力，而 TLR4 可能是 HMGB1 对 CD4+CD25+Tregs 活性产生负性影响的潜在必需受体。
