CIP2A Promotes T-Cell Activation and Immune Response to Listeria monocytogenes Infection.
The oncoprotein Cancerous Inhibitor of Protein Phosphatase 2A (CIP2A) is overexpressed in most malignancies and is an obvious candidate target protein for future cancer therapies. However, the physiological importance of CIP2A-mediated PP2A inhibition is largely unknown. As PP2A regulates immune responses, we investigated the role of CIP2A in normal immune system development and during immune response in vivo. We show that CIP2A-deficient mice (CIP2AHOZ) present a normal immune system development and function in unchallenged conditions. However when challenged with Listeria monocytogenes, CIP2AHOZ mice display an impaired adaptive immune response that is combined with decreased frequency of both CD4+ T-cells and CD8+ effector T-cells. Importantly, the cell autonomous effect of CIP2A deficiency for T-cell activation was confirmed. Induction of CIP2A expression during T-cell activation was dependent on Zap70 activity. Thus, we reveal CIP2A as a hitherto unrecognized mediator of T-cell activation during adaptive immune response. These results also reveal CIP2AHOZ as a possible novel mouse model for studying the role of PP2A activity in immune regulation. On the other hand, the results also indicate that CIP2A targeting cancer therapies would not cause serious immunological side-effects.
Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, Turku, Finland.
Christophe
http://orcid.org/0000-0001-5229-4440
C
Côme
Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, Turku, Finland.
Anna
A
Cvrljevic
Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, Turku, Finland.|Turku Doctoral Programme of Molecular Medicine (TuDMM), Medical Faculty, University of Turku, Turku, Finland.
Mohd Moin
MM
Khan
German Mouse Clinic, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.|Institute for Medical Microbiology, Immunology and Hygiene, Technische Universität München, Munich, Germany.|Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
Irina
I
Treise
German Mouse Clinic, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.|Institute for Medical Microbiology, Immunology and Hygiene, Technische Universität München, Munich, Germany.
Thure
T
Adler
German Mouse Clinic, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.|Department of Dermatology and Allergy, Biederstein, Klinikum rechts der Isar, Technische Universität München (TUM), Munich, Germany.
Juan Antonio
JA
Aguilar-Pimentel
Howard Hughes Medical Institute, Rosalind Russell Medical Research Center for Arthritis, Department of Medicine, Department of Microbiology and Immunology, University of California San Francisco, San Francisco, California, United States of America.
Byron
B
Au-Yeung
Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, Turku, Finland.
Eleonora
E
Sittig
Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, Turku, Finland.|Department of Mathematics and Statistics, University of Turku, Turku, Finland.
Teemu Daniel
TD
Laajala
Howard Hughes Medical Institute, Rosalind Russell Medical Research Center for Arthritis, Department of Medicine, Department of Microbiology and Immunology, University of California San Francisco, San Francisco, California, United States of America.
Yiling
Y
Chen
Center of Allergy and Environment Munich (ZAUM), Technische Universität München (TUM), and Institute for Allergy Research, Helmholtz Zentrum München, German Research Center for Environmental Health, Munich/Neuherberg, Germany.|Kühne Foundation, Christine Kühne Center for Allergy Research and Education (CK-CARE), Munich, Germany.
Sebastian
S
Oeder
German Mouse Clinic, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.|Institute of Pathology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
Julia
J
Calzada-Wack
German Mouse Clinic, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.|Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
Marion
M
Horsch
Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.
Tero
T
Aittokallio
Institute for Medical Microbiology, Immunology and Hygiene, Technische Universität München, Munich, Germany.
Dirk H
DH
Busch
Clinical Research Group Molecular Allergology, Center of Allergy and Environment Munich (ZAUM), Technische Universität München (TUM), and Institute for Allergy Research, Helmholtz Zentrum München, German Research Center for Environmental Health, Munich/Neuherberg, Germany.
Markus W
MW
Ollert
German Mouse Clinic, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.|Institute of Pathology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
Frauke
F
Neff
German Mouse Clinic, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.|Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.|Chair of Experimental Genetics, Center for Life and Food Sciences Weihenstephan, Technische Universität München, Freising-Weihenstephan, Germany.
Johannes
J
Beckers
German Mouse Clinic, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.|Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
Valerie
V
Gailus-Durner
German Mouse Clinic, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.|Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
Helmut
H
Fuchs
German Mouse Clinic, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.|Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.|German Center for Diabetes Research (DZD), Neuherberg, Germany.
Martin
M
Hrabě de Angelis
Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, Turku, Finland.
Zhi
Z
Chen
Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, Turku, Finland.
Riitta
R
Lahesmaa
Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, Turku, Finland.|Department of Pathology, University of Turku, Turku, Finland.
Jukka
J
Westermarck
D000818:Animals; D001324:Autoantigens / Q000276:immunology*; D005260:Female; D007109:Immunity / Q000276:immunology*; D008089:Listeria monocytogenes / Q000276:immunology*; D008088:Listeriosis / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology*; D008297:Male; D008565:Membrane Proteins / Q000276:immunology*; D051379:Mice; D013601:T-Lymphocytes / Q000276:immunology*
D001324:Autoantigens; C573112:KIAA1524 protein, mouse; D008565:Membrane Proteins