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

Simon Völkl, Anne Rensing-Ehl, Andrea Allgäuer, Elisabeth Schreiner, Myriam Ricarda Lorenz, Jan Rohr, Christian Klemann, Ilka Fuchs, Volker Schuster, André O. Von Bueren, Nora Naumann-Bartsch, Eleonora Gambineri, Kathrin Siepermann, Robin Kobbe, Michaela Nathrath, Peter D. Arkwright, Maurizio Miano, Klaus-Daniel Stachel, Markus Metzler, Klaus SchwarzAnita N Kremer, Carsten Speckmann, Stephan Ehl, Andreas Mackensen

Research output: Contribution to journalArticle

Abstract

Autoimmune lymphoproliferative syndrome (ALPS) is a human disorder characterized by defective Fas signaling, resulting in chronic benign lymphoproliferation and accumulation of TCRαβ(+) CD4(-) CD8(-) double-negative T (DNT) cells. Although their phenotype resembles that of terminally differentiated or exhausted T cells, lack of KLRG1, high eomesodermin, and marginal T-bet expression point instead to a long-lived memory state with potent proliferative capacity. Here we show that despite their terminally differentiated phenotype, human ALPS DNT cells exhibit substantial mitotic activity in vivo. Notably, hyperproliferation of ALPS DNT cells is associated with increased basal and activation-induced phosphorylation of serine-threonine kinases Akt and mechanistic target of rapamycin (mTOR). The mTOR inhibitor rapamycin abrogated survival and proliferation of ALPS DNT cells, but not of CD4(+) or CD8(+) T cells in vitro. In vivo, mTOR inhibition reduced proliferation and abnormal differentiation by DNT cells. Importantly, increased mitotic activity and hyperactive mTOR signaling was also observed in recently defined CD4(+) or CD8(+) precursor DNT cells, and mTOR inhibition specifically reduced these cells in vivo, indicating abnormal programming of Fas-deficient T cells before the DNT stage. Thus, our results identify the mTOR pathway as a major regulator of lymphoproliferation and aberrant differentiation in ALPS.

Original languageEnglish
Pages (from-to)227-38
Number of pages12
JournalBlood
Volume128
Issue number2
DOIs
Publication statusPublished - Jul 14 2016

Keywords

  • Journal Article

Fingerprint Dive into the research topics of 'Hyperactive mTOR pathway promotes lymphoproliferation and abnormal differentiation in autoimmune lymphoproliferative syndrome'. Together they form a unique fingerprint.

  • Cite this

    Völkl, S., Rensing-Ehl, A., Allgäuer, A., Schreiner, E., Lorenz, M. R., Rohr, J., Klemann, C., Fuchs, I., Schuster, V., Von Bueren, A. O., Naumann-Bartsch, N., Gambineri, E., Siepermann, K., Kobbe, R., Nathrath, M., Arkwright, P. D., Miano, M., Stachel, K-D., Metzler, M., ... Mackensen, A. (2016). Hyperactive mTOR pathway promotes lymphoproliferation and abnormal differentiation in autoimmune lymphoproliferative syndrome. Blood, 128(2), 227-38. https://doi.org/10.1182/blood-2015-11-685024