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J Exp Med. 2016 May 2;213(5):841-57. doi: 10.1084/jem.20150794. Epub 2016 Apr 11.

CD1d-restricted peripheral T cell lymphoma in mice and humans.

Author information

1
CIRI, International Center for Infectiology Research, Université de Lyon, 69007 Lyon, France Institut National de la Santé et de la Recherche Médicale (INSERM), U1111, 69007 Lyon, France Ecole Normale Supérieure de Lyon, 69007 Lyon, France Université Lyon 1, Centre International de Recherche en Infectiologie, 69007 Lyon, France Centre National de la Recherche Scientifique (CNRS), UMR 5308, 69365 Lyon, France Department of Hematology, Hospices Civils de Lyon, 69004 Lyon, France Université de Lyon, Université Claude Bernard Lyon1, 69007 Lyon, France.
2
CIRI, International Center for Infectiology Research, Université de Lyon, 69007 Lyon, France Institut National de la Santé et de la Recherche Médicale (INSERM), U1111, 69007 Lyon, France Ecole Normale Supérieure de Lyon, 69007 Lyon, France Université Lyon 1, Centre International de Recherche en Infectiologie, 69007 Lyon, France Centre National de la Recherche Scientifique (CNRS), UMR 5308, 69365 Lyon, France.
3
Division of Developmental Immunology, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037.
4
AltraBio SAS, 69007 Lyon, France.
5
Department of Pathology, Hospices Civils de Lyon, 69004 Lyon, France CNRS, UMR 5239, 69342 Lyon, France.
6
Department of Cytogenetics, Hospices Civils de Lyon, 69004 Lyon, France CNRS, UMR 5239, 69342 Lyon, France.
7
Institut Albert Bonniot, INSERM U823, Université J. Fourier, 38041 Grenoble, France.
8
Department of Cytology, Hospices Civils de Lyon, 69004 Lyon, France CNRS, UMR 5239, 69342 Lyon, France.
9
Department of Pathology and Microbiology, Center for Lymphoma and Leukemia Research, University of Nebraska Medical Center, Omaha, NE 68198.
10
Laboratory of Lymphocyte Signaling and Oncoproteome, Department I of Internal Medicine, Center for Integrated Oncology Köln-Bonn, and Excellence Cluster for Cellular Stress Response and Aging-Associated Diseases, University of Cologne, 50923 Cologne, Germany.
11
INSERM U955, Créteil 94000, France Université Paris-Est, Créteil 94000, France Department of Pathology, AP-HP, Groupe Henri-Mondor Albert-Chenevier, 94000 Créteil, France.
12
Department of Dermatology, Centre Hospitalier Lyon-Sud, Hospices Civils de Lyon, 69004 Lyon, France University Claude Bernard Lyon 1, 69100 Lyon, France INSERM UMR-S1052, CNRS UMR 5286, Centre de Recherche en Cancérologie de Lyon, 69003 Lyon, France.
13
Service d'Hématologie Biologique, Groupe Hospitalier Pitié-Salpêtrière, Sorbonne Universités, UPMC, Université Paris 06 et Assistance Publique-Hôpitaux de Paris, 75004 Paris, France INSERM U1138, Programmed cell death and physiopathology of tumor cells, Centre de Recherche des Cordeliers, 75006 Paris, France.
14
Department of Hematology, Hospices Civils de Lyon, 69004 Lyon, France Université de Lyon, Université Claude Bernard Lyon1, 69007 Lyon, France CNRS, UMR 5239, 69342 Lyon, France.
15
Université de Lyon, Université Claude Bernard Lyon1, 69007 Lyon, France INSERM UMR-S1052, CNRS UMR 5286, Centre de Recherche en Cancérologie de Lyon, 69003 Lyon, France ProfileXpert, SFR Santé Lyon-Est, UCBL UMS 3453 CNRS-US7 INSERM, 69372 Lyon, France.
16
Institut Imagine, Laboratoire INSERM, Unité Mixte de Recherche 1163, CNRS Équipe de Recherche Laboratoryéllisée 8254, Cellular and Molecular Basis of Hematological Disorders and Therapeutic Implications, 75015 Paris, France Service d'Hématologie, Faculté de Médecine Paris Descartes, Sorbonne Paris-Cité et Assistance Publique-Hôpitaux de Paris Hôpital Necker, 75015 Paris, France.
17
Université Paris Descartes Sorbonne Cité, Institut Necker-Enfants Malades, INSERM U1151, and Laboratory of Onco-Hematology, Assistance Publique-Hôpitaux de Paris, Hôpital Necker Enfants-Malades, 75015 Paris, France.
18
Rennes University Hospital, Rennes INSERM UMR 917 Faculté de Médecine Université Rennes 1, 35000 Rennes, France.
19
CIRI, International Center for Infectiology Research, Université de Lyon, 69007 Lyon, France Institut National de la Santé et de la Recherche Médicale (INSERM), U1111, 69007 Lyon, France Ecole Normale Supérieure de Lyon, 69007 Lyon, France Université Lyon 1, Centre International de Recherche en Infectiologie, 69007 Lyon, France Centre National de la Recherche Scientifique (CNRS), UMR 5308, 69365 Lyon, France laurent.genestier@inserm.fr.

Abstract

Peripheral T cell lymphomas (PTCLs) are a heterogeneous entity of neoplasms with poor prognosis, lack of effective therapies, and a largely unknown pathophysiology. Identifying the mechanism of lymphomagenesis and cell-of-origin from which PTCLs arise is crucial for the development of efficient treatment strategies. In addition to the well-described thymic lymphomas, we found that p53-deficient mice also developed mature PTCLs that did not originate from conventional T cells but from CD1d-restricted NKT cells. PTCLs showed phenotypic features of activated NKT cells, such as PD-1 up-regulation and loss of NK1.1 expression. Injections of heat-killed Streptococcus pneumonia, known to express glycolipid antigens activating NKT cells, increased the incidence of these PTCLs, whereas Escherichia coli injection did not. Gene expression profile analyses indicated a significant down-regulation of genes in the TCR signaling pathway in PTCL, a common feature of chronically activated T cells. Targeting TCR signaling pathway in lymphoma cells, either with cyclosporine A or anti-CD1d blocking antibody, prolonged mice survival. Importantly, we identified human CD1d-restricted lymphoma cells within Vδ1 TCR-expressing PTCL. These results define a new subtype of PTCL and pave the way for the development of blocking anti-CD1d antibody for therapeutic purposes in humans.

PMID:
27069116
PMCID:
PMC4854725
DOI:
10.1084/jem.20150794
[Indexed for MEDLINE]
Free PMC Article

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