REGULATION OF IL4 SECRETION BY INVARIANT T CELLS

胰腺自身反应性T细胞对胰岛β细胞的消融 I型糖尿病被认为是一种复杂的相互作用的结果 在遗传因素和环境因素之间。在人类疾病中，不完整 同卵双胞胎之间的一致性表明除了 基因对疾病的发展起到了作用。(1)最近的研究 人类和小鼠的自身免疫性疾病已经证明了 和/或不寻常的CD4或CD4-CD8-人群中的质量缺陷， 使用不变TCRpha(Valpha24JalphaQ)链的NKRP1 T细胞 与TCR Vbeta链的受限曲目配对。(2)(3)这些 细胞有独特的能力分泌大量的 白介素4(IL-4)而不事先启动IL-4，因此，是一种 早期IL-4的候选来源被认为对T细胞的偏向很重要 细胞对Th2表型的反应，而不是前... 1型糖尿病患者的炎症性Th1表型。配基 由这些潜在的调节性T细胞识别的是CD1d。(4) CD1d和不变T细胞使用的TCRs的显著保守性 老鼠和人类之间的关系表明这些细胞具有重要的功能 在免疫反应过程中。在一项关于同卵双胞胎不和谐的研究中 我们证明，1型糖尿病患者的数量减少了 不变T细胞与克隆细胞产生IL-4的显著缺陷 源自糖尿病兄弟姐妹。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Valpha24JalphaQ T细胞克隆 从不协调双胞胎到比较和对比信号事件和基因 在TCR参与后发生的表达模式，以便识别 糖尿病患者IL-4分泌缺陷的原因(S) 双胞胎。

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.