Development and function of regulatory T cells

调节性 T 细胞的发育和功能

• 批准号: 10926130
• 负责人: Alfred Singer
• 金额: $ 35.09万
• 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/10926130
• 关键词: Apoptotic; Autoimmunity; CD28 gene; CTLA4 gene; Cell membrane; Cell physiology; Cells; Development; FOXP3 gene; Generations; IL2RA gene; Immune; Interleukin-2; Mature Thymocyte; Pathway interactions; Regulatory T-Lymphocyte; Signal Transduction; System; Thymus Gland; cytokine; peripheral lymphoid organ; prevent; transcription factor

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. This year we discovered that the Foxp3 transcription factor is pro-apoptotic and lethal to developing Tregs unless the Treg cells are signaled by IL-2 or other pro-survival cytokines. Because IL-2 is limiting in the thymus, 80-90% of newly arising Tregs that arise in the thymus fail to survive development and fail to become mature Tregs. In addition, this discovery reveals the existence of two alternative Treg developmental pathways in the thymus by which developing thymocytes mature into functional Tregs.

B7/CD28共刺激是胸腺产生功能成熟的CD4+CD25+Foxp3+调节性T细胞所必需的。然而，尚不清楚B7/CD28共刺激是否也是维持外周调节功能所必需的。我们开发了一个实验系统，其中B7/CD28共刺激在胸腺中可用来诱导Foxp3+Treg细胞的产生，但在Treg细胞所在的外周缺乏B7/CD28共刺激。我们发现，外周淋巴器官的持续共刺激是维持Treg细胞低反应性和调节功能所必需的，它通过维持Treg细胞中CTLA-4的高水平表达。我们还发现CTLA-4在Tregs中紧密定位于细胞膜下，这种独特的分布有助于其有效地抑制TCR信号，并有助于诱导Tregs的低反应和调节功能。我们的结果表明，通过持续的共刺激维持Treg细胞中CTLA-4的高水平表达是Treg细胞功能的关键。今年，我们发现Foxp3转录因子对发育中的Treg细胞是促凋亡和致死的，除非Treg细胞被IL-2或其他促进生存的细胞因子发出信号。由于IL-2局限于胸腺，在胸腺中产生的新生的Treg细胞中有80%-90%无法存活发育，也无法成为成熟的Treg细胞。此外，这一发现揭示了胸腺中存在两条可供选择的Treg发育途径，通过这两条途径，发育中的胸腺细胞成熟为功能Treg。