ALPS DNT cells: active senior living with mTOR

In this issue of Blood,Völkl and colleagues report extended phenotypic and functional analysis of double-negative T cells in autoimmune lymphoproliferative syndrome (ALPS), and find that these cells not only resist cell death but also maintain increased mitotic activity dependent on mechanistic target of rapamycin (mTOR) signaling.¹ 

ALPS is a condition characterized by defective apoptotic mechanisms that disrupt lymphocyte homeostasis. Failure to cull lymphocytes—particularly the characteristic TCRαβ⁺ double-negative (CD4^– CD8^–) T (DNT) cells—results in lymphadenopathy and hepatosplenomegaly, may lead to autoimmune disorders, and may also increase the risk of lymphoma. ALPS is most commonly associated with germline mutations in FAS, though a much smaller number of patients has been associated with inherited mutations in FASLG and CASP10, or somatic mutations in FAS. Approximately 20% of cases have no identifiable genetic abnormality.²  The need for consensus statements with diagnostic criteria, including “definitive” or “probable” modifiers, indicates the evolving complexity of the ALPS diagnosis as an end point arrived at through many potential pathways and with variable penetrance.³  Front-line therapy for clinically problematic lymphoproliferation has historically been corticosteroids.^2,4  Sirolimus (rapamycin), which targets the PI3K/Akt/mTOR signaling pathway,⁵  has been demonstrated to have superior activity compared with other drugs in a mouse model of ALPS.⁶  In a recent prospective clinical trial, treatment of ALPS patients with massive lymphoproliferation with sirolimus led not only to clinical improvement, but also to normalization of DNT cell populations.⁷ 

In this issue, Völkl and colleagues investigate the activity of DNT cells in ALPS. Surprisingly, they found that ALPS DNTs are not simply exhausted cells that refuse to die; these terminally differentiated cells exhibit substantial mitotic activity that is dependent on activation of Akt and mTOR. Sirolimus treatment in vivo reduced proliferation and abnormal differentiation of DNT cells. In addition, the authors identified mTOR-dependent proliferation in CD4⁺ and CD8⁺ DNT precursors, indicating some signs of mischief in Fas-deficient T cells, even before the DNT stage. These findings demonstrate that ALPS DNT cells are not simply accumulating in retiring senescence. Rather, ALPS DNT cells and DNT cell precursors remain active and proliferate under the influence of activated mTOR signaling (Figure 7 in Völkl et al). Although mTOR is activated in other conditions, such as PIK3CD gain-of-function mutations,⁸  uncoupling of cell survival and proliferation appears unique to ALPS. These stubborn cells may provide an opportunity to further explore the roles of mTOR in T-lymphocyte differentiation and function.