Hyperactive mTOR pathway promotes lymphoproliferation and abnormal differentiation in autoimmune lymphoproliferative syndrome.
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.
Department of Internal Medicine 5, Haematology and Oncology, University Hospital Erlangen, Erlanger, Germany;
Simon
S
Völkl
Center for Chronic Immunodeficiency, University Medical Center Freiburg, University of Freiburg, Freiburg, Germany;
Anne
A
Rensing-Ehl
Department of Internal Medicine 5, Haematology and Oncology, University Hospital Erlangen, Erlanger, Germany;
Andrea
A
Allgäuer
Department of Internal Medicine 5, Haematology and Oncology, University Hospital Erlangen, Erlanger, Germany;
Elisabeth
E
Schreiner
Institute for Transfusion Medicine, University of Ulm, Ulm, Germany;
Myriam Ricarda
MR
Lorenz
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;
Jan
J
Rohr
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;
Christian
C
Klemann
Center for Chronic Immunodeficiency, University Medical Center Freiburg, University of Freiburg, Freiburg, Germany;
Ilka
I
Fuchs
Hospital for Children and Adolescents, University of Leipzig, Leipzig, Germany;
Volker
V
Schuster
Division of Pediatric Haematology and Oncology, Department of Pediatric and Adolescent Medicine, University Medical Center Göttingen, Göttingen, Germany;
André O
AO
von Bueren
Department of Pediatrics, University Hospital Erlangen, Erlangen, Germany;
Nora
N
Naumann-Bartsch
Department of Neuroscience, Psychology, Drug Area and Child Health (NEUROFARBA), Section of Child's Health, University of Florence, Florence, Italy;
Eleonora
E
Gambineri
Department of Pediatric and Adolescent Medicine, HELIOS Klinikum Krefeld, Krefeld, Germany;
Kathrin
K
Siepermann
Department of Pediatrics, University Medical Centre Hamburg, Hamburg, Germany;
Robin
R
Kobbe
Department of Pediatric Oncology, Klinikum Kassel, Kassel, Germany; Department of Pediatrics, Pediatric Oncology Center, Technische Universität München, Munich, Germany;
Michaela
M
Nathrath
Department of Pediatric Allergy and Immunology, Royal Manchester Children's Hospital, University of Manchester, Manchester, United Kingdom;
Peter D
PD
Arkwright
Clinical and Experimental Haematology Unit, Giannina Gaslini Children's Hospital, Genoa, Italy; and.
Maurizio
M
Miano
Department of Pediatrics, University Hospital Erlangen, Erlangen, Germany;
Klaus-Daniel
KD
Stachel
Department of Pediatrics, University Hospital Erlangen, Erlangen, Germany;
Markus
M
Metzler
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;
Klaus
K
Schwarz
Department of Internal Medicine 5, Haematology and Oncology, University Hospital Erlangen, Erlanger, Germany;
Anita N
AN
Kremer
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.
Carsten
C
Speckmann
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.
Stephan
S
Ehl
Department of Internal Medicine 5, Haematology and Oncology, University Hospital Erlangen, Erlanger, Germany;
Andreas
A
Mackensen
D000293:Adolescent; D000328:Adult; D056735:Autoimmune Lymphoproliferative Syndrome / Q000276:immunology* / Q000473:pathology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D002454:Cell Differentiation / Q000276:immunology*; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D037181:Lectins, C-Type / Q000276:immunology; D017493:Leukocyte Common Antigens / Q000276:immunology; D008297:Male; D051057:Proto-Oncogene Proteins c-akt / Q000276:immunology; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D011971:Receptors, Immunologic; D015398:Signal Transduction / Q000276:immunology*; D058570:TOR Serine-Threonine Kinases / Q000276:immunology*; D015534:Trans-Activators / Q000276:immunology
C113413:KLRG1 protein, human; D037181:Lectins, C-Type; D011948:Receptors, Antigen, T-Cell; D011971:Receptors, Immunologic; D015534:Trans-Activators; C546842:MTOR protein, human; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D017493:Leukocyte Common Antigens