REGULATION OF IL4 SECRETION BY INVARIANT T CELLS

恒定 T 细胞对 IL4 分泌的调节

• 批准号: 2835440
• 负责人: S. Brian BRIAN Wilson
• 金额: $ 16.32万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-04-01 至 2004-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2835440
• 关键词: CD3 molecule; T cell receptor; T lymphocyte; apoptosis; biological signal transduction; calcium flux; clone cells; gene expression; genetic techniques; human genetic material tag; insulin dependent diabetes mellitus; interleukin 4; monozygotic twins; pathologic process; phosphatidylinositol 3 kinase; phospholipase C; protein biosynthesis; secretion

The ablation of pancreatic beta cells by autoreactive T cells seen in Type I diabetes is thought to be the result of a complex interplay between genetic and environmental factors. In human disease, incomplete concordance between identical twins suggests that factors other than genetics contribute to disease progression. (1) Recent studies of autoimmune diseases in humans and mice have demonstrated quantitative and/or qualitative defects in an unusual population of CD4+ or CD4-CD8-, NKRP1+ T cells that use an invariant TCRalpha (Valpha24JalphaQ) chain paired with a restricted repertoire of TCR Vbeta chains. (2)(3) These cells have the unique capability to secrete large amounts of interleukin-4 (IL-4) without prior IL-4 priming, and as such, are a candidate source of early IL-4 thought to be important in biasing a T cell response towards a Th2 phenotype, and away from the pro- inflammatory Th1 phenotype seen in Type 1 diabetes. The ligand recognized by these potentially regulatory T cells is CD1d. (4) The striking conservation of CD1d and the TCRs used by invariant T cells between mice and humans indicate an important function for these cells during an immune response. In a study of identical twins discordant for Type 1 diabetes we demonstrated that there were reduced numbers of invariant T cells and a striking defect in IL-4 production in clones derived from the diabetic siblings. We hypothesize that IL-4 specific changes in TCR signaling pathways occurred during the progression to Type 1 diabetes. We propose to use Valpha24JalphaQ T cell clones raised from discordant twins to compare and contrast signaling events and gene expression patterns occurring after TCR engagement in order to identify the reason(s) for the defect in IL-4 secretion seen in the diabetic twin.

胰腺β细胞被自身反应性T细胞消融， I型糖尿病被认为是一个复杂的相互作用的结果 遗传和环境因素之间的关系。在人类疾病中， 同卵双胞胎之间的一致性表明， 遗传学有助于疾病进展。(1)最近的研究 人类和小鼠的自身免疫性疾病已经证明了定量的 和/或不寻常的CD 4+或CD 4-CD 8-群体中的质量缺陷， 使用恒定TCR α（Valpha 24 JalphaQ）链的NKRP 1 + T细胞 与TCR V β链的限制性库配对。（2）（3）这些 细胞具有分泌大量 白细胞介素-4（IL-4），而没有预先IL-4引发，因此，是一种 早期IL-4的候选来源被认为是重要的偏置T 细胞对Th 2表型的反应，而远离亲- 1型糖尿病中观察到的炎性Th 1表型。配体 被这些潜在的调节性T细胞识别的是CD 1d。(4)的 恒定T细胞使用的CD 1d和TCR的惊人保守性 表明了这些细胞的重要功能 在免疫反应中。在一项对同卵双胞胎的研究中， 我们证明了1型糖尿病患者中， 克隆中不变T细胞和IL-4产生的显著缺陷 来自糖尿病患者的兄弟姐妹。我们假设IL-4特异性 TCR信号通路的变化发生在进展到 1型糖尿病我们建议使用产生的Valpha 24 JalphaQ T细胞克隆， 从不一致的双胞胎中比较和对比信号事件和基因 在TCR接合后发生的表达模式，以鉴定 在糖尿病患者中观察到的IL-4分泌缺陷的原因 双胞胎姐姐