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Author Notes:

E-mail: christophe.come@bric.ku.dk

Conceived and designed the experiments: CC AC JB DB JCW MO VGD HF MHdA RL JW.

Performed the experiments: CC AC MMK IT T. Adler JAAP BAY ES YC SO JCW MH ZC.

Analyzed the data: CC AC MMK IT T. Adler JAAP BAY ES TDL YC SO JCW MH T. Aittokallio FN ZC JW.

Contributed reagents/materials/analysis tools: CC AC MMK IT T.

Adler JAAP BAY ES TDL YC SO JCW MH ZC.

Wrote the paper: CC AC IT T. Adler JAAP BAY TDL JCW MH FN ZC JW.

The authors have declared that no competing interests exist.

The authors are grateful for German Mouse Clinic (GMC) and Turku Center for Disease modelling (TCDM) animal caretakers for expert technical assistance.

We thank also Dr. Olli Lassila for expert advice. We further thank Christine Gau for statistic support and Anke Bettenbrock, Erika Nyman, Taina Kalevo-Mattila, Inga Pukonen, Marjo Hakkarainen, Sarita Heinonen, Päivi Junni, Elina Pietilä, Elenore Samson and Jacqueline Mueller for excellent technical support.

The Finnish Microarray and Sequencing Centre is thanked for their technical assistance. We would like to acknowledge voluntary blood donors and Department of Obstetrics and Gynecology, Maternity Ward staff members, Turku university hospital, Turku Finland, for cord blood collection.

We thank Chao Zhang and Kevan Shokat for providing the Zap70(AS) analogue inhibitor HXJ42.

Subjects:

Research Funding:

This study was supported by grants from the Academy of Finland (http://www.aka.fi/fi/; grants 121413, 122546, 258313 and 137687, 133227, 140880, 269862, 272437), Sigrid Juselius Foundation (http://sigridjuselius.net/), Turku Doctoral Programme of Molecular Medicine (TuDMM; http://www.utu.fi/en/units/med/studying/postgrad/doctoral/doctoralprogrammes/tudmm/Pages/home.aspx), Foundation for the Finnish Cancer Institute (http://syopasaatio.fi/), the German Federal Ministry of Education and Research (http://www.bmbf.de/; Infrafrontier grant 01KX1012), German National Genome Research Network (BMBF-NGFN project 01GS0868 to MO) and the Seventh Framework Programme of the European Commission (http://cordis.europa.eu/fp7/home_en.html; FP7-SYBILLA-201106).

Keywords:

  • Science & Technology
  • Multidisciplinary Sciences
  • Science & Technology - Other Topics
  • PROTEIN PHOSPHATASE 2A
  • CATALYTIC-ACTIVITY
  • CANCER
  • APOPTOSIS
  • PP2A
  • ONCOPROTEIN
  • INHIBITOR
  • KINASE
  • ZAP70

CIP2A Promotes T-Cell Activation and Immune Response to Listeria monocytogenes Infection

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Journal Title:

PLoS ONE

Volume:

Volume 11, Number 4

Publisher:

, Pages e0152996-e0152996

Type of Work:

Article | Final Publisher PDF

Abstract:

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 (CIP2A HOZ ) present a normal immune system development and function in unchallenged conditions. However when challenged with Listeria monocytogenes, CIP2A HOZ 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 CIP2A HOZ 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.

Copyright information:

© 2016 Côme et al.

This is an Open Access work distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/).
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