PMID- 27099149
OWN - NLM
STAT- MEDLINE
DCOM- 20170803
LR  - 20220316
IS  - 1528-0020 (Electronic)
IS  - 0006-4971 (Linking)
VI  - 128
IP  - 2
DP  - 2016 Jul 14
TI  - Hyperactive mTOR pathway promotes lymphoproliferation and abnormal 
      differentiation in autoimmune lymphoproliferative syndrome.
PG  - 227-38
LID - 10.1182/blood-2015-11-685024 [doi]
AB  - Autoimmune lymphoproliferative syndrome (ALPS) is a human disorder characterized 
      by defective Fas signaling, resulting in chronic benign lymphoproliferation and 
      accumulation of TCRalphabeta(+) 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.
CI  - (c) 2016 by The American Society of Hematology.
FAU - Volkl, Simon
AU  - Volkl S
AD  - Department of Internal Medicine 5, Haematology and Oncology, University Hospital 
      Erlangen, Erlanger, Germany;
FAU - Rensing-Ehl, Anne
AU  - Rensing-Ehl A
AD  - Center for Chronic Immunodeficiency, University Medical Center Freiburg, 
      University of Freiburg, Freiburg, Germany;
FAU - Allgauer, Andrea
AU  - Allgauer A
AD  - Department of Internal Medicine 5, Haematology and Oncology, University Hospital 
      Erlangen, Erlanger, Germany;
FAU - Schreiner, Elisabeth
AU  - Schreiner E
AD  - Department of Internal Medicine 5, Haematology and Oncology, University Hospital 
      Erlangen, Erlanger, Germany;
FAU - Lorenz, Myriam Ricarda
AU  - Lorenz MR
AD  - Institute for Transfusion Medicine, University of Ulm, Ulm, Germany;
FAU - Rohr, Jan
AU  - Rohr J
AD  - 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;
FAU - Klemann, Christian
AU  - Klemann C
AD  - 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;
FAU - Fuchs, Ilka
AU  - Fuchs I
AD  - Center for Chronic Immunodeficiency, University Medical Center Freiburg, 
      University of Freiburg, Freiburg, Germany;
FAU - Schuster, Volker
AU  - Schuster V
AD  - Hospital for Children and Adolescents, University of Leipzig, Leipzig, Germany;
FAU - von Bueren, Andre O
AU  - von Bueren AO
AD  - Division of Pediatric Haematology and Oncology, Department of Pediatric and 
      Adolescent Medicine, University Medical Center Gottingen, Gottingen, Germany;
FAU - Naumann-Bartsch, Nora
AU  - Naumann-Bartsch N
AD  - Department of Pediatrics, University Hospital Erlangen, Erlangen, Germany;
FAU - Gambineri, Eleonora
AU  - Gambineri E
AD  - Department of Neuroscience, Psychology, Drug Area and Child Health (NEUROFARBA), 
      Section of Child's Health, University of Florence, Florence, Italy;
FAU - Siepermann, Kathrin
AU  - Siepermann K
AD  - Department of Pediatric and Adolescent Medicine, HELIOS Klinikum Krefeld, 
      Krefeld, Germany;
FAU - Kobbe, Robin
AU  - Kobbe R
AD  - Department of Pediatrics, University Medical Centre Hamburg, Hamburg, Germany;
FAU - Nathrath, Michaela
AU  - Nathrath M
AD  - Department of Pediatric Oncology, Klinikum Kassel, Kassel, Germany; Department of 
      Pediatrics, Pediatric Oncology Center, Technische Universitat Munchen, Munich, 
      Germany;
FAU - Arkwright, Peter D
AU  - Arkwright PD
AD  - Department of Pediatric Allergy and Immunology, Royal Manchester Children's 
      Hospital, University of Manchester, Manchester, United Kingdom;
FAU - Miano, Maurizio
AU  - Miano M
AD  - Clinical and Experimental Haematology Unit, Giannina Gaslini Children's Hospital, 
      Genoa, Italy; and.
FAU - Stachel, Klaus-Daniel
AU  - Stachel KD
AD  - Department of Pediatrics, University Hospital Erlangen, Erlangen, Germany;
FAU - Metzler, Markus
AU  - Metzler M
AD  - Department of Pediatrics, University Hospital Erlangen, Erlangen, Germany;
FAU - Schwarz, Klaus
AU  - Schwarz K
AD  - 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;
FAU - Kremer, Anita N
AU  - Kremer AN
AD  - Department of Internal Medicine 5, Haematology and Oncology, University Hospital 
      Erlangen, Erlanger, Germany;
FAU - Speckmann, Carsten
AU  - Speckmann C
AD  - 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.
FAU - Ehl, Stephan
AU  - Ehl S
AD  - 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.
FAU - Mackensen, Andreas
AU  - Mackensen A
AD  - Department of Internal Medicine 5, Haematology and Oncology, University Hospital 
      Erlangen, Erlanger, Germany;
LA  - eng
PT  - Clinical Trial
PT  - Journal Article
PT  - Multicenter Study
DEP - 20160420
PL  - United States
TA  - Blood
JT  - Blood
JID - 7603509
RN  - 0 (KLRG1 protein, human)
RN  - 0 (Lectins, C-Type)
RN  - 0 (Receptors, Antigen, T-Cell)
RN  - 0 (Receptors, Immunologic)
RN  - 0 (Trans-Activators)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 3.1.3.48 (Leukocyte Common Antigens)
SB  - IM
CIN - Blood. 2016 Jul 14;128(2):152. PMID: 27418624
MH  - Adolescent
MH  - Adult
MH  - Autoimmune Lymphoproliferative Syndrome/*immunology/pathology
MH  - CD4-Positive T-Lymphocytes/*immunology/pathology
MH  - CD8-Positive T-Lymphocytes/*immunology/pathology
MH  - Cell Differentiation/*immunology
MH  - Child
MH  - Child, Preschool
MH  - Female
MH  - Humans
MH  - Lectins, C-Type/immunology
MH  - Leukocyte Common Antigens/immunology
MH  - Male
MH  - Proto-Oncogene Proteins c-akt/immunology
MH  - Receptors, Antigen, T-Cell/immunology
MH  - Receptors, Immunologic
MH  - Signal Transduction/*immunology
MH  - TOR Serine-Threonine Kinases/*immunology
MH  - Trans-Activators/immunology
EDAT- 2016/04/22 06:00
MHDA- 2017/08/05 06:00
CRDT- 2016/04/22 06:00
PHST- 2015/11/30 00:00 [received]
PHST- 2016/04/14 00:00 [accepted]
PHST- 2016/04/22 06:00 [entrez]
PHST- 2016/04/22 06:00 [pubmed]
PHST- 2017/08/05 06:00 [medline]
AID - S0006-4971(20)34360-3 [pii]
AID - 10.1182/blood-2015-11-685024 [doi]
PST - ppublish
SO  - Blood. 2016 Jul 14;128(2):227-38. doi: 10.1182/blood-2015-11-685024. Epub 2016 
      Apr 20.