All-trans retinoic acid (ATRA) induces miR-23a expression, decreases CTSC expression and granzyme B activity leading to impaired NK cell cytotoxicity.
NK cell is an innate immune system lymphocyte lineage with natural cytotoxicity. Its optimal use in the clinic requires in vitro expansion and activation. Cytokines and encounter with target cells activate NK cells and induce proliferation, and this could depend on the presence of other immune cells. Here we activated PBMCs during 5 days with IL-2, with IL-2 plus the tumor cell line K562 and with the lymphoblastoid cell line R69 and perform integrated analyses of microRNA and mRNA expression profiles of purified NK cells. The samples cluster depending on the stimuli and not on the donor, indicating that the pattern of NK cell stimulation is acutely well conserved between individuals. Regulation of mRNA expression is tighter than that of miRNA expression. All stimuli induce a common preserved genetic remodeling. In addition, encounter with target cells mainly activates pathways related to metabolism. Different target cells induce different NK cell remodeling which affects cytokine response and cytotoxicity, supporting the notion that encounter with different target cells significantly changing the activation pattern. We validate our analysis by showing that activation down regulates miR-23a, which is a negative regulator of cathepsin C (CTSC) mRNA, a gene up regulated by all stimuli. The peptidase CTSC activates the granzymes, the main effector proteases involved in NK cell cytotoxicity. All-trans retinoic acid (ATRA), which induces miR-23a expression, decreases CTSC expression and granzyme B activity leading to impaired NK cell cytotoxicity in an in vivo mouse model.
Cell Immunity in Cancer, Inflammation and infection Group, Biomedical Research Center of Aragon (CIBA), Nanoscience Institute of Aragon (INA), Aragon I+D Foundation (ARAID), IIS Aragon/University of Zaragoza, Zaragoza 50009, Spain.
Diego
D
Sanchez-Martínez
INSERM U1040, Université de Montpellier 1, UFR Médecine, Montpellier F-34295, France.
Ewelina
E
Krzywinska
INSERM U1040, Université de Montpellier 1, UFR Médecine, Montpellier F-34295, France.
Moeez G
MG
Rathore
Institut de Recherche en Cancérologie de Montpellier INSERM U896, Université Montpellier 1, CRLC Val d'Aurelle Paul Lamarque, Montpellier F-34298, France.
Anne
A
Saumet
INSERM U1040, Université de Montpellier 1, UFR Médecine, Montpellier F-34295, France.
Amelie
A
Cornillon
INSERM U1040, Université de Montpellier 1, UFR Médecine, Montpellier F-34295, France.
Nuria
N
Lopez-Royuela
Apoptosis, Immunity and Cancer Group, Department Biochemistry and Molecular and Cell Biology, Faculty of Sciences, University of Zaragoza, Zaragoza 50009, Spain.
Luis
L
Martínez-Lostao
Apoptosis, Immunity and Cancer Group, Department Biochemistry and Molecular and Cell Biology, Faculty of Sciences, University of Zaragoza, Zaragoza 50009, Spain.
Ariel
A
Ramirez-Labrada
INSERM U1040, Université de Montpellier 1, UFR Médecine, Montpellier F-34295, France.
Zhao-Yang
ZY
Lu
INSERM U1040, Université de Montpellier 1, UFR Médecine, Montpellier F-34295, France.
Jean-François
JF
Rossi
Progenika Biopharma SA, Parque Tecnológico Bizkaia 504, 48160 Derio, Bizkaia, Spain.
Dietmar
D
Fernández-Orth
Progenika Biopharma SA, Parque Tecnológico Bizkaia 504, 48160 Derio, Bizkaia, Spain.
Sergio
S
Escorza
Apoptosis, Immunity and Cancer Group, Department Biochemistry and Molecular and Cell Biology, Faculty of Sciences, University of Zaragoza, Zaragoza 50009, Spain.
Alberto
A
Anel
Institut de Génétique Moléculaire de Montpellier UMR 5535 CNRS, 1919 route de Mende, 34293 Montpellier cedex 5, France. Université Montpellier 2, Place Eugène Bataillon, 34095 Montpellier cedex 5, France. Université Montpellier 1, 5 Bd Henry IV, 34967 Montpellier Cedex 2, France.
Charles-Henri
CH
Lecellier
Cell Immunity in Cancer, Inflammation and infection Group, Biomedical Research Center of Aragon (CIBA), Nanoscience Institute of Aragon (INA), Aragon I+D Foundation (ARAID), IIS Aragon/University of Zaragoza, Zaragoza 50009, Spain.
Julian
J
Pardo
INSERM U1040, Université de Montpellier 1, UFR Médecine, Montpellier F-34295, France; Institut de Recherche en Biothérapie (IRB), CHU Montpellier, Montpellier 34295, France. Electronic address: martin.villalba@inserm.fr.
Martin
M
Villalba
D000818:Animals; D015153:Blotting, Western; D020789:Cathepsin C / Q000235:genetics* / Q000378:metabolism; D002460:Cell Line; D002478:Cells, Cultured; D016000:Cluster Analysis; D003602:Cytotoxicity, Immunologic / Q000187:drug effects*; D005260:Female; D053804:Granzymes / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007376:Interleukin-2 / Q000494:pharmacology; D019169:Jurkat Cells; D020014:K562 Cells; D007694:Killer Cells, Natural / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D025341:Principal Component Analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D059467:Transcriptome / Q000187:drug effects / Q000235:genetics; D014212:Tretinoin / Q000494:pharmacology*
D007376:Interleukin-2; C552430:MIRN23a microRNA, human; D035683:MicroRNAs; C534062:Mirn23b microRNA, mouse; D014212:Tretinoin; D020789:Cathepsin C; C533919:Ctsc protein, mouse; D053804:Granzymes
Cathepsin C; NK cells; Transcriptomics; miR-23a; miRNA