COACTIVATION SIGNALS REGULATE THYMOCYTE DEVELOPMENT

共激活信号调节胸腺细胞的发育

• 批准号: 6839930
• 负责人: DAVID J MCKEAN
• 金额: $ 28.22万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-02-01 至 2006-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6839930
• 关键词: CD2 molecule; CD28 molecule; T cell receptor; T lymphocyte; apoptosis; biological signal transduction; cell differentiation; genetically modified animals; laboratory mouse; lymphopoiesis; organ culture; thymus; tissue /cell culture

DESCRIPTION: (Adapted from applicant's abstract) T cell development in the thymus occurs as a sequential process from double negative (CD4-CD8- TcR-) to double positive (CD4+ CD8+ TcR+) to single positive (CD4+ CD8-, CD4- CD8+) cells. During the double positive to single positive transition antigen receptors on thymocytes initiate signals that select for cells with appropriate self/non-self recognition. Thymocytes that express receptors with no affinity for MHC/antigen die by neglect, cells with high affinity for self antigens die by apoptosis and cells with low affinity for self antigens undergo further differentiation. TCR signals alone do not effectively regulate positive and negative selection. Thymic development is also regulated by receptors capable of providing "second signals" to TcR- activated cells. This project will characterize the activation responses initiated in DP thymocytes as a result of engaging TCR and CD28 and/or CD2 co-inducer receptors. These two sets of stimuli are being used as model agonists to comparatively characterize signaling pathways that regulate maturation or apoptosis. The nature and strength of the response initiated by these co-inducer receptors determines whether TCR-activated DP thymocytes mature to CD4+ CD8- cells or undergo apoptosis. Maturation and apoptotic responses stimulated by signals from TCR + CD28 are independent and separable components in the thymocyte maturation program. In addition, TCR engagement in DP thymocytes induces the expression of novel co-inducer receptors that stimulate arrest of thymocyte maturation. These analyses will determine how signals integrated from different co-inducer receptors stimulate cross-talk between signaling pathways that affects the outcome of thymocyte selection.

描述：（改编自申请人的摘要）T细胞开发 胸腺作为从双重阴性（CD4-CD8-TCR-）到的顺序过程。 单个正（CD4+ CD8-，CD4- CD8+）的双阳性（CD4+ CD8+ TCR+） 细胞。在双阳性到单个正过渡抗原期间 胸腺细胞上的受体启动信号，以选择适当的细胞 自我/非自我识别。表达无亲和力的受体的胸腺细胞 对于MHC/抗原因忽视而死，对自抗原具有高亲和力的细胞死亡 通过凋亡和对自抗原亲和力低的细胞进一步经历 分化。单独的TCR信号不会有效地调节阳性和 负选择。胸腺发育也受受体的调节 向TCR活化细胞提供“第二个信号”。这个项目将 表征由于DP胸腺细胞引发的激活反应 参与TCR和CD28和/或CD2共同诱导者受体。这两套 刺激被用作模型激动剂，以相对表征 调节成熟或凋亡的信号通路。自然和 这些共同诱导者受体引发的反应的强度决定了 TCR激活的DP胸腺细胞成熟到CD4+ CD8-细胞还是经历 凋亡。 TCR +信号刺激的成熟和凋亡反应 CD28是胸腺细胞成熟的独立和可分离的成分 程序。此外，DP胸腺细胞中的TCR参与诱导 刺激胸腺细胞成熟的停滞的新型共同诱导者受体。这些 分析将确定如何从不同共同诱导者集成的信号 受体刺激影响影响的信号通路之间的串扰 胸腺细胞选择的结果。

项目成果

Increased thymic output in HIV-negative patients after antiretroviral therapy.

HIV阴性患者抗逆转录病毒治疗后胸腺输出增加。

• DOI: 10.1097/01.aids.0000182520.69159.8a
• 发表时间: 2005
• 期刊: AIDS (London, England)
• 作者: Graham,DanielB;Bell,MichaelP;Huntoon,CatherineJ;Weaver,JoelGR;Hawley,Nanci;Badley,AndrewD;McKean,DavidJ
• 通讯作者: McKean,DavidJ