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: 10262228
• 负责人: Alfred Singer
• 金额: $ 36.85万
• 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/10262228
• 关键词: CD8B1 gene; Cell Lineage; Cells; Cues; Cytokine Signaling; 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; cytotoxic CD8 T cells; 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.

传统的T细胞发育观点认为，来自同一T细胞受体(TCR)的信号决定了向成熟的CD4+辅助细胞和CD8+细胞毒细胞的阳性和阴性选择以及谱系选择。实现这一点的确切机制仍然存在争议，但有人提出，TCR信号的数量或质量上的差异可以解释谱系选择的不同结果。与这些观点相反，我们在这里表明，仅有TCR信号不足以决定发育中的胸腺细胞的细胞命运，而且CD4/CD8谱系的选择需要白细胞介素7(IL-7)等细胞因子的额外提示。通过有条件地删除IL-7受体的直接下游信号分子，我们证明了在体内，IL-7诱导的细胞因子信号对于CD8谱系的选择和向成熟的CD8+细胞毒性T细胞的分化是必需的。我们的数据确立了体内IL-7和其他伽马c-细胞因子在未成熟胸腺细胞CD8谱系承诺中的先前未被认识的作用，这与T细胞谱系选择的动力学信号模型一致。我们最近还发现了非伽马c-细胞因子(IL-6、TSLP和IFNGamma)在CD8谱系承诺中的意外作用，并正在积极分析它们在胸腺阳性选择过程中的作用模式。