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

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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.