Hyperactive mTOR pathway promotes lymphoproliferation and abnormal differentiation in autoimmune lymphoproliferative syndrome

Abstract

Key Points ALPS DNT cells and their putative precursors reveal high proliferative activity in vivo, which is associated with hyperactive mTOR signaling. Rapamycin therapy controls mitotic activity and abnormal differentiation of ALPS DNT cells and reduces CD4+ or CD8+ precursor DNT cells.

Dual Role of Fas/FasL-Mediated Signal in Peripheral Immune Tolerance

“…Peripheral T cells expressing TCRα/β, but not CD4 and CD8 [CD4 − CD8 − double negative (DN)], proliferate, and their population expands in the patients with ALPS due to an impaired AICD caused by a defect in the Fas/FasL system (98). Further, the abnormal programming of Fas-deficient T cells before the DN T-stage is caused by impaired signaling through the mTOR pathway (99). Moreover, a defect in B-cell selection occurs in patients with ALPS, which is caused by impaired class-switch recombination and somatic hypermutation of the genes encoding immunoglobulins (100).…”

Evolution of disease activity and biomarkers on and off rapamycin in 28 patients with autoimmune lymphoproliferative syndrome

“…Lymphoproliferation in ALPS is not just due to an accumulation of DNT cells that cannot die, but these cells and their single positive precursor cells 8 are highly proliferative in vivo. 6,9 This proliferative activity is associated with hyperactive mTOR signaling.…”

“…As described, 3,6 DNT cells rapidly decreased upon rapamycin treatment, but only 7 of 25 patients (33%) reached normal percentages ( Figure 1A). IL-10 levels decreased, but remained more than 20 pg/mL in 14 of 23 patients (61%) ( Figure 1C).…”

“…6,7 The rapid relapse of disease after stopping treatment indicates that the cells giving rise to DNT cells are either not fully eliminated or are rapidly regenerated once targeted mTOR inhibition is stopped. How rapamycin abrogates autoimmune manifestations remains unclear.…”

“…Christian Klemann, 1,2* Myrian Esquivel, 3,4* Aude Magerus-Chatinet, 3,5 Myriam R. Lorenz, 6,7 Ilka Fuchs, 1 Nathalie Neveux, 8 Martin Castelle, 4 Jan Rohr, 1,2 Claudia Bettoni da Cunha, 9 Martin Ebinger, 10 Robin Kobbe, 11 Bernhard Kremens, 12 Florian Kollert, 13 Eleonora Gambineri, 14 Kai Lehmberg, 15 3,4,20 Alain Fischer, 3,4,21 Frederic Rieux-Laucat, 3,5 Stephan Ehl, …”