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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 (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.
Highlights
Despite a considerable improvement in cancer treatment efficiency in the last decade, infectious complications will lead to morbidity and mortality of many patients [1, 2]
We report here that Cancerous Inhibitor of Protein Phosphatase 2A (CIP2A) expression is a novel mechanism important for optimal in vivo adaptive immune response after Listeria monocytogenes (L.m.) re-infection
CIP2A expression was not detected in lymphoid tissues from CIP2AHOZ mice (Fig 1A and 1B and S1A Fig) indicating that CIP2A is efficiently deleted in this genetrap mouse model
Summary
Despite a considerable improvement in cancer treatment efficiency in the last decade, infectious complications will lead to morbidity and mortality of many patients [1, 2] These infections, occurring in solid organ tumors and more frequently in hematological malignancies, are often related to treatment-induced immunosuppression [3]. To identify novel physiological functions for CIP2A, CIP2AHOZ mouse model was subjected to a systemic phenotyping screen at the German Mouse Clinic [17, 18], including thorough immunological characterization. We report here that CIP2A expression is a novel mechanism important for optimal in vivo adaptive immune response after Listeria monocytogenes (L.m.) re-infection. These data may have importance in the evaluation of potential immunological effects of future CIP2A-targeted cancer therapies
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