CIP2A promotes T-cell activation and immune response to Listeria monocytogenes infection
Open accessAbstract
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.
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Reduction of CIP2A levels resulted in differential expression of genes associated with regulation of autoimmune diseases, although these mice showed normal immune system development and no immunological defects under baseline conditions.
“reduction of CIP2A levels resulted in a differential expression of genes associated with regulation of autoimmune diseases, although these mice showed normal immune system development and did not display any immunological defects under baseline conditions [83].”
From Physiologic functions of PP2A: Lessons from genetically modified mice (2019) · cites this paper as [83]
In wild-type T-cells, CIP2A expression was induced after anti-CD3/anti-CD28 stimulation, implying a role for CIP2A in T-cell activation, particularly of effector CD8+ T-cells.
“In WT T-cells, CIP2A expression was induced after anti-CD3/anti-CD28 stimulation, further implying a role of CIP2A in T-cell activation, particularly of effector CD8 + T-cells [83].”
From Physiologic functions of PP2A: Lessons from genetically modified mice (2019) · cites this paper as [83]
When challenged with Listeria monocytogenes, CIP2A-deficient mice had an impaired adaptive immune response, with reduced numbers of CD4+ T-cells, CD8+ effector T-cells, and IFNγ-producing CD8+ T-cells, indicating reduced proliferation of CIP2A-deficient T-cells.
“when challenged with Listeria monocytogenes, an impaired adaptive immune response was provoked, with reduced numbers of CD4 + T-cells, CD8 + effector T-cells and IFNγ-producing CD8 + T-cells, indicative for reduced proliferation of CIP2A-deficient T-cells.”
From Physiologic functions of PP2A: Lessons from genetically modified mice (2019) · cites this paper as [83]
PP2A is involved in CD4+ T-cell activation and differentiation.
“Notably, several studies have demonstrated that PP2A is involved in CD4 + T-cell activation and differentiation [ 284 , 285 ].”
From Targeting PP2A in cancer: an underrated option (2025) · cites this paper as [285]
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- Authors
- Côme, C., Cvrljevic, A., Khan, M. M., Treise, I., Adler, T., Aguilar-Pimentel, J. A., Au-Yeung, B., Sittig, E., Laajala, T. D., Chen, Y., Oeder, S., Calzada-Wack, J., Horsch, M., Aittokallio, T., Busch, D. H., Ollert, M. W., Neff, F., Beckers, J., Gailus-Durner, V., Fuchs, H., de Angelis, M. H., Chen, Z., Lahesmaa, R., & Westermarck, J.
- Affiliations
- Åbo Akademi University (FI)
- Helmholtz Munich (DE)
- University of Helsinki (FI)
- Technical University of Munich (DE)
- ORCID
- Venue
- PLoS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2016-04-21
- Volume
- 11
- Issue
- 4
- Pages
- e0152996
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC4839633
- OpenAlex
- W2338601250
- Cited by
- 20
- References
- 37
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- 2025: 2 · 2024: 1 · 2023: 2 · 2022: 2 · 2020: 2 · 2019: 3 · 2018: 4 · 2017: 3 · 2016: 1
- FWCI
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- Language
- en
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- gold
- doi.org
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- Funders
- Suomen Akatemia (122546, 258313, 121413, 137687, 133227, 140880, 269862, 272437)
- Sigrid Juséliuksen Säätiö
- Turun Yliopisto
- Suomen Lääketieteen Säätiö
- Bundesministerium für Bildung und Forschung (Infrafrontier grant 01KX1012, German National Genome Research Network (BMBF-NGFN project 01GS0868 to MO))
- Seventh Framework Programme (FP7-SYBILLA-201106)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Signaling Pathways in Disease
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
- Keywords
- CIP2A, protein phosphatase 2A, T cell activation, Listeria monocytogenes infection, adaptive immune response, CD4+ T cells, CD8+ effector T cells, ZAP-70, immune regulation, immunotherapy side effects
- MeSH terms
- Animals, Autoantigens, Female, Immunity, Listeriosis, Listeria monocytogenes, Lymphocyte Activation, Male, Membrane Proteins, T-Lymphocytes, Mice
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