Hyperactive mTOR Pathway Promotes Lymphoproliferation and Abnormal Differentiation in Human Autoimmune Lymphoproliferative Syndrome

Autoimmune lymphoproliferative syndrome (ALPS) is a complex genetic disorder characterized by defective Fas apoptosis pathway, resulting in chronic benign lymphoproliferation and accumulation of TCRαβ+ CD4- CD8- double-negative (DN) T cells. These aberrant cells express the surface molecules CD45RA and CD57 and lack expression of CCR7 and CD127, suggesting terminal differentiation or exhaustion of DN T cells. However, high eomesodermin and marginal T-bet expression and lack of killer cell lectin-like receptor G1 (KLRG1) rather point to a long-lived memory state with potent proliferative capacity. The relevance of this discrepancy, their underlying signaling pathways and the resulting functional properties remain poorly understood. Here we show that despite their terminal differentiated phenotype human ALPS DN T cells exhibit substantial mitotic activity in vivo. Notably, baseline and activation induced phosphorylation of serine-threonine kinases Akt and mTOR was markedly increased in DN T cells from ALPS patients. The mTOR inhibitor rapamycin (sirolimus) abrogated survival and proliferation of DN T cells but not of CD4+ or CD8+ T cells in vitro. In vivo, mTOR inhibition reduced proliferation and abnormal differentiation and abolished production of IL-10 and FasL by DN T cells. Taken together, this work uncovers the importance of mTOR signaling as a critical regulator of lymphoproliferation and accumulation of aberrant DN T cells in human ALPS and underlines the importance of therapeutic modulation of this pathway.