Development and function of regulatory T cells

调节性 T 细胞的发育和功能

• 批准号: 8552987
• 负责人: Alfred Singer
• 金额: $ 35.71万
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8552987
• 关键词: Autoimmunity; CD28 gene; Cell membrane; Cell physiology; Cells; Development; Generations; IL2RA gene; Immune; Lymphoid; Organ; Peripheral; Regulatory T-Lymphocyte; Signal Transduction; System; Thymus Gland; prevent

B7/CD28 costimulation is required to generate functional mature CD4+CD25+Foxp3+ regulatory T cells in the thymus. However, its not known whether B7/CD28 costimulation is also required to maintain regulatory function in the periphery. We developed an experimental system in which B7/CD28 costimulation was available in the thymus to induce the generation of Foxp3+ Treg cells, but B7/CD28 costimulation was absent from the periphery where Treg cells resided. We discovered that persistent costimulation in peripheral lymphoid organ is required to maintain Treg cell hyporesponsiveness and regulatory function through maintaining high level CTLA-4 expression in Tregs. We also found that CTLA-4 in Tregs is closely localized under the cytoplasmic membrane and this unique distribution facilitates its efficient inhibition of TCR signaling and contributes to the induction of hyporesponsiveness and regulatory function in Tregs. Our results indicate that maintaining high level expression of CTLA-4 in Tregs by persistent costimulation is critical for Treg cell function.

B7/CD 28共刺激是胸腺中产生功能性成熟CD 4 + CD 25 + Foxp 3+调节性T细胞所必需的。然而，目前尚不清楚B7/CD 28共刺激是否也需要维持外周的调节功能。我们开发了一种实验系统，其中B7/CD 28共刺激可在胸腺中诱导Foxp 3 + Treg细胞的产生，但B7/CD 28共刺激不存在于Treg细胞所在的外周。我们发现外周淋巴器官中持续的共刺激是通过维持T细胞中高水平的CTLA-4表达来维持Treg细胞低反应性和调节功能所必需的。我们还发现，CTLA-4在T细胞中紧密定位于细胞质膜下，这种独特的分布有助于其有效抑制TCR信号传导，并有助于诱导T细胞中的低反应性和调节功能。我们的研究结果表明，通过持续的共刺激来维持CTLA-4在Treg细胞中的高水平表达对Treg细胞功能至关重要。