THE FUNCTION OF T-BET IN T HELPER CELL DEVELOPMENT

在持续的免疫应答中，幼稚的辅助性T前体（Thp）细胞分化为两种谱系之一，Th1或Th2，其特征是表达特定的细胞因子。这种极性介导了几种人类疾病发病机制和抑制之间的平衡，包括过敏；自身免疫和感染；然而，Th1发育的分子基础在很大程度上仍然未知。最近，一种新的蛋白T-bet （T细胞中表达的T-box）被分离出来，并发现它对Th1细胞具有高度选择性，尽管它也存在于胸腺细胞、NK细胞和B细胞中。有趣的是，T-bet是转录因子T-box家族的一员，该家族在很大程度上与胚胎发育有关。该蛋白的表达足以将Th1表型赋予Thp和极化Th2细胞，这表明它在谱系承诺中起着重要作用：该应用建议通过培养T-bet基因突变小鼠（Aim 1），鉴定T-bet的调节因子和效应因子（Aim 2），并了解其在疾病状态中的潜在作用（Aim 3）来分析T-bet的生物学功能。

During ongoing immune responses, naive helper T precursor (Thp) cells differentiate into one of two lineages, Th1 or Th2, characterized by the expression of particular cytokines. This polarity mediates the balance between disease pathogenesis and suppression in several human conditions, including allergy; autoimmunity, and infection; however, the molecular basis of Th1 development remains largely unknown. Recently, a novel protein, T-bet (T-box expressed in T cells), has been isolated and found highly selective for Th1 cells, though it is also found in thymocytes, as well as NK and B cells. Interestingly, T-bet is a member of the T-box family of transcription factors, which have largely been implicated in embryonic development. Expression of this protein is sufficient to confer the Th1 phenotype upon both Thp and polarized Th2 cells, suggesting that it plays a substantial role in Th lineage commitment: This application proposes to analyze the biological function of T-bet by developing T-bet genetic mutant mice (Aim 1), identifying regulators and effectors of T-bet (Aim 2), and understanding its potential role in disease states (Aim 3).