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

Voelkl S, Rensing-Ehl A, Allgäuer A, Schreiner E, Lorenz MR, Rohr J, Klemann C, Fuchs I, Schuster V, Von Bueren AO, Naumann-Bartsch N, Gambineri E, Siepermann K, Kobbe R, Nathrath M, Arkwright PD, Miano M, Stachel D, Metzler M, Schwarz K, Kremer A, Speckmann C, Ehl S, Mackensen A (2016)

Publication Type: Journal article

Publication year: 2016

Journal

Blood American Society of Hematology

Book Volume: 128

Pages Range: 227-38

Journal Issue: 2

DOI: 10.1182/blood-2015-11-685024

Abstract

Autoimmune lymphoproliferative syndrome (ALPS) is a human disorder characterized by defective Fas signaling, resulting in chronic benign lymphoproliferation and accumulation of TCR??(+) 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.

Authors with CRIS profile

Andrea Allgäuer Department of Medicine 5 – Haematology and Oncology Klaus Daniel Stachel Medizinische Fakultät Markus Metzler Professur für Kinder- und Jugendmedizin mit dem Schwerpunkt Pädiatrische Onkologie und Hämatologie Anita Kremer Department of Medicine 5 – Haematology and Oncology Andreas Mackensen Lehrstuhl für Innere Medizin V

Involved external institutions

Albert-Ludwigs-Universität Freiburg DE Germany (DE) Istituto Giannina Gaslini IT Italy (IT) University of Manchester GB United Kingdom (GB) Klinikum Kassel GmbH DE Germany (DE) Universitätsklinikum Hamburg-Eppendorf (UKE) DE Germany (DE) HELIOS Kliniken DE Germany (DE) Università degli Studi di Firenze / University of Florence IT Italy (IT) Universitätsklinikum Göttingen DE Germany (DE) Universität Leipzig DE Germany (DE) Universität Ulm DE Germany (DE)

How to cite

APA:

Voelkl, S., Rensing-Ehl, A., Allgäuer, A., Schreiner, E., Lorenz, M.R., Rohr, J.,... Mackensen, A. (2016). Hyperactive mTOR pathway promotes lymphoproliferation and abnormal differentiation in autoimmune lymphoproliferative syndrome. Blood, 128(2), 227-38. https://dx.doi.org/10.1182/blood-2015-11-685024

MLA:

Voelkl, Simon, et al. "Hyperactive mTOR pathway promotes lymphoproliferation and abnormal differentiation in autoimmune lymphoproliferative syndrome." Blood 128.2 (2016): 227-38.

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