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Blood. 2016 Jul 14;128(2):227-38. doi: 10.1182/blood-2015-11-685024. Epub 2016 Apr 20.

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

Author information

1
Department of Internal Medicine 5, Haematology and Oncology, University Hospital Erlangen, Erlanger, Germany;
2
Center for Chronic Immunodeficiency, University Medical Center Freiburg, University of Freiburg, Freiburg, Germany;
3
Institute for Transfusion Medicine, University of Ulm, Ulm, Germany;
4
Center for Chronic Immunodeficiency, University Medical Center Freiburg, University of Freiburg, Freiburg, Germany; Institute for Clinical Transfusion Medicine and Immunogenetics Ulm, German Red Cross Blood Service, Ulm, Germany;
5
Hospital for Children and Adolescents, University of Leipzig, Leipzig, Germany;
6
Division of Pediatric Haematology and Oncology, Department of Pediatric and Adolescent Medicine, University Medical Center Göttingen, Göttingen, Germany;
7
Department of Pediatrics, University Hospital Erlangen, Erlangen, Germany;
8
Department of Neuroscience, Psychology, Drug Area and Child Health (NEUROFARBA), Section of Child's Health, University of Florence, Florence, Italy;
9
Department of Pediatric and Adolescent Medicine, HELIOS Klinikum Krefeld, Krefeld, Germany;
10
Department of Pediatrics, University Medical Centre Hamburg, Hamburg, Germany;
11
Department of Pediatric Oncology, Klinikum Kassel, Kassel, Germany; Department of Pediatrics, Pediatric Oncology Center, Technische Universität München, Munich, Germany;
12
Department of Pediatric Allergy and Immunology, Royal Manchester Children's Hospital, University of Manchester, Manchester, United Kingdom;
13
Clinical and Experimental Haematology Unit, Giannina Gaslini Children's Hospital, Genoa, Italy; and.
14
Center for Chronic Immunodeficiency, University Medical Center Freiburg, University of Freiburg, Freiburg, Germany; Institute for Transfusion Medicine, University of Ulm, Ulm, Germany; Institute for Clinical Transfusion Medicine and Immunogenetics Ulm, German Red Cross Blood Service, Ulm, Germany;
15
Center for Chronic Immunodeficiency, University Medical Center Freiburg, University of Freiburg, Freiburg, Germany; Center for Paediatrics and Adolescent Medicine, University Medical Center, University of Freiburg, Freiburg, Germany.

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.

PMID:
27099149
DOI:
10.1182/blood-2015-11-685024
[Indexed for MEDLINE]
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