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

自身免疫性淋巴组织增生综合征（ALPS）是一种罕见的人类疾病，其特征在于凋亡机制缺陷，导致慢性良性淋巴组织增生、自身免疫表现和CD 3 + TCRab+ CD 4-/CD 8-双阴性T（DNT）细胞的积累。尽管是这种疾病的标志，但ALPS中DNT细胞的起源和功能仍不清楚。基于淋巴细胞稳态失调，DNT细胞在ALPS中的积累最初被认为是衰老细胞在其生命周期结束时受损死亡的结果。我们发现特异性DNT细胞表现出异常的表型，具有分化的效应细胞和长寿命记忆细胞的特征。此外，我们证明了ALPS患者的DNT细胞在体内是高度增殖的。增强的有丝分裂活性与mTOR通路的过度激活相关。在这个项目中，我们的目标是确定ALPS DNT细胞中导致过度活跃的mTOR通路和增强的增殖活性的潜在信号传导过程。此外，我们打算表征DNT细胞在ALPS患者中的功能。最后，我们将分析异常T细胞群是否也可在患有ALPS样疾病的患者中检测到（例如Caspase 8缺陷状态，STAT 3功能获得性，活化PI 3 K δ综合征）以及这些子集具有哪些特征。总之，这些分析将使我们更好地了解免疫缺陷的病理机制和新的靶向治疗的发展。

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.