The oncoprotein Cancerous Inhibitor of Protein Phosphatase 2A (CIP2A) has been documented to be a clinically relevant oncoprotein in the majority of solid and hematological human cancers. It 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 the target of CIP2A, PP2A, regulates immune responses. The scientists around Christoph Côme from the University of Turku and Åbo Akademi University, Turku, Finland, investigated the role of CIP2A in normal immune system development and during immune response in vivo.
Apart from the tumor suppressor activity the scientists were interested in the functions in the development and functioning of the immune system. Therefore wild type and CIP2A-deficient (CIP2AHOZ) mice were analyzed in detail in the German Mouse Clinic.
The histological analysis revealed no pathological alterations between wild type and CIP2AHOZ mice in 42 different organs. Additionally the CIP2A deficiency did not induce changes in distributions of the main leukocyte populations in lymphoid organs. The analysis of the gene expression profile of the spleen from CIP2AHOZ mice revealed differential expression of genes related to the regulation of immune response and/or autoimmune diseases. Since in an unchallenged situation the mice showed no problems regarding the immune system, the scientists used functional in vivo assays and challenging experiments.
Wild type and CIP2AHOZ mice were immunized with ovalbumin in order to measure the T-cell-dependent antibody response. Compared to wild type mice, the induction of peanut agglutinin (PNA) positivity and proliferation in germinal centers was attenuated in CIP2AHOZ mice indicating a role of CIP2A within the T-cell dependent B-cell response.
As innate and adaptive immune responses are required for the clearance of intracellular bacteria Listeria monocytogenes, wild type and CIP2AHOZ mice were infected with L.m. These experiments showed that the adaptive immune response in CIP2a-deficient mice was reduced. Further in vitro experiments confirmed that CIP2A promotes T-cell activation in a cell-autonomous fashion.
Christophe Côme, Anna Cvrljevic, Mohd Moin Khan, Irina Treise, Thure Adler, Juan Antonio Aguilar-Pimentel, Byron Au-Yeung, Eleonora Sittig, Teemu Daniel Laajala, Yiling Chen, Sebastian Oeder, Julia Calzada-Wack, Marion Horsch, Tero Aittokallio, Dirk H. Busch, Markus W. Ollert, Frauke Neff, Johannes Beckers, Valerie Gailus-Durner, Helmut Fuchs, Martin Hrabě de Angelis, Zhi Chen, Riitta Lahesmaa, Jukka Westermarck. CIP2A Promotes T-Cell Activation and Immune Response to Listeria monocytogenes Infection. 2016. PLoS ONE 11(4): e0152996. Doi: dx.doi.org/10.1371/journal.pone.0152996