Importance of aberrant double negative T-cells in patients with autoimmune lymphoproliferative syndrome (ALPS)

自身免疫淋巴增殖性综合征(Alps)是一种罕见的人类疾病，其特征是细胞凋亡机制缺陷，导致慢性良性淋巴组织增生，自身免疫表现和CD3+TCRab+CD4-/CD8-双阴性T细胞(DNT)聚集。尽管是这种疾病的标志，但阿尔卑斯山的DNT细胞的来源和功能尚不清楚。在淋巴细胞稳态失调的基础上，DNT细胞在阿尔卑斯山的积聚最初被认为是由于衰老细胞在生命周期结束时的损伤死亡所致。我们发现致病的DNT细胞表现出异常的表型，既具有分化的效应细胞的特征，又具有长寿命记忆细胞的特征。此外，我们还证实了阿尔卑斯病患者的DNT细胞在体内高度增殖。有丝分裂活性的增强与mTOR通路的过度激活有关。在这个项目中，我们的目标是确定Alps DNT细胞中导致mTOR途径过度活跃和增殖活性增强的潜在信号过程。此外，我们打算表征阿尔卑斯病患者的DNT细胞的功能。最后，我们将分析在阿尔卑斯样疾病患者中是否也可以检测到异常的T细胞群(例如，Caspase 8缺乏状态、STAT3功能获得、激活的PI3K增量综合征)，以及这些亚群具有哪些特征。总之，这些分析将使人们更好地了解免疫缺陷的发病机制，并开发新的靶向治疗方法。

Autoimmune lymphoproliferative syndrome (ALPS) is a rare human disorder characterized by defective apoptotic mechanisms, resulting in chronic benign lymphoproliferation, autoimmune manifestations and accumulation of CD3+ TCRab+ CD4-/CD8- double negative T (DNT) cells. Despite being a hallmark of this disease, the origin and function of DNT cells in ALPS is widely unknown. On the basis of dysregulated lymphocyte homeostasis, the accumulation of DNT cells in ALPS was initially considered to result from impaired death of senescent cells at the end of their life cycle. We found that pathognomonic DNT cells show an abnormal phenotype with features of both differentiated effector cells and long-lived memory cells. Moreover, we demonstrated that DNT cells of ALPS patients are highly proliferative in vivo. Enhanced mitotic activity was associated with hyperactivation of the mTOR pathway. In this project we aim to identify the underlying signaling processes in ALPS DNT cells leading to the hyperactive mTOR pathway and enhanced proliferative activity. Moreover, we intend to characterize the functionality of DNT cells in patients with ALPS. Finally, we will analyze whether aberrant T cell populations are also detectable in patients with ALPS-like disorders (e.g. Caspase 8-deficiency state, STAT3 gain-of-function, Activated-PI3K delta syndrome) and which features these subsets possess. Together, these analyses will allow a better understanding of the pathomechanisms of immune deficiencies and the development of novel targeted therapies.