Cytokine signaling in developing thymocytes and T cells

发育中的胸腺细胞和 T 细胞中的细胞因子信号传导

• 批准号: 10014532
• 负责人: Alfred Singer
• 金额: $ 28.48万
• 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/10014532
• 关键词: CD8B1 gene; Cell Lineage; Cells; Cues; Cytokine Signaling; Cytotoxic T-Lymphocytes; Data; Disputes; Goals; Interleukin 7 Receptor; Interleukin-6; Interleukin-7; Kinetics; Malignant Neoplasms; Mature T-Lymphocyte; Modality; Modeling; Natural Killer Cells; Outcome; Receptor Signaling; Role; Signal Transduction; Signaling Molecule; Specificity; T-Cell Development; T-Cell Receptor; T-Lymphocyte; TSLP gene; Therapeutic; Thymus Gland; cytokine; in vivo; thymocyte

The conventional view on T cell development posits that signals from the same T cell receptor (TCR) determines both positive and negative selection as well as lineage choice into mature CD4+ helper and CD8+ cytotoxic cells. The precise mechanism how this is achieved is still under dispute but it has been proposed that either quantitative or qualitative differences in TCR signaling would account for the different outcomes of lineage choice. In contrast to such views, here we show that TCR signaling alone is not sufficient to determine cell fate of developing thymocytes, and that CD4/CD8 lineage choice requires additional cues by cytokines such as interleukin-7 (IL-7). Using conditional deletion of immediate downstream signaling molecules of the IL-7 receptor, we demonstrate that IL-7 induced cytokine signals are required for CD8 lineage choice and for the differentiation into mature CD8+ cytotoxic T cells in vivo. Our data establish a previously unappreciated role for in vivo IL-7 and other gamma c-cytokines in CD8 lineage commitment of immature thymocytes, which is consistent with the kinetic signaling model of T cell lineage choice. We have recently also identified an unexpected role for non-gamma c-cytokines (IL-6, TSLP, and IFNgamma) in CD8 lineage commitment and are actively analyzing their mode of action during positive selection in the thymus.

对T细胞发育的常规视图认为，来自同一T细胞受体（TCR）的信号决定了正选择和负选择，以及对成熟的CD4+助手和CD8+细胞毒性细胞的谱系选择。如何实现这一目标的确切机制仍在争议中，但已提出，TCR信号传导中的定量或定性差异将解释谱系选择的不同结果。与这种观点相反，我们在这里表明，仅TCR信号传导不足以确定发育中的胸腺细胞的细胞命运，并且CD4/CD8谱系选择需要诸如interleukin-7（IL-7）等细胞因子的其他线索。使用IL-7受体的立即下游信号分子的条件缺失，我们证明了CD8谱系选择需要IL-7诱导的细胞因子信号，并将分化为体内的成熟CD8+细胞毒性T细胞。我们的数据在不成熟胸腺细胞的CD8谱系承诺中为体内IL-7和其他γc-胞素的作用建立了先前未批准的作用，这与T细胞谱系选择的动力学信号传导模型一致。最近，我们还确定了非γc-伴侣（IL-6，TSLP和IFNGAMMA）在CD8谱系承诺中的意外作用，并正在积极分析其在胸腺阳性选择期间的作用方式。