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Deletion of cIAP1 and cIAP2 in murine B lymphocytes constitutively activates cell survival pathways and inactivates the germinal center response

Abstract

B cells require signals delivered through BAFF-R and CD40 to survive and produce antibody responses in vivo. In vitro data indicates that these signals are controlled by the homologous RING finger proteins cIAP1 and cIAP2, in collaboration with TRAF2 and TRAF3. There is also mounting evidence that all four of these signalling molecules can act as tumor suppressors in human B-lineage malignancies. However, it has not been possible to identify the roles of cIAP1 and cIAP2 in controlling B cell physiology due to the absence of an appropriate in vivo model. Here we describe a unique genetically modified mouse in which the linked cIap1 and cIap2 genes can be independently inactivated. Deletion of cIAP1 plus cIAP2 (but not either protein alone) rendered primary B cells independent of BAFF-R for their survival and led to their uncontrolled accumulation in vivo. B cells deficient in cIAP1 and cIAP2 were also incapable of forming germinal centers, a key step in antibody-mediated immunity. Our data define a fundamental role for cIAP1/cIAP2 in regulating B cell survival and responsiveness, show this requires direct binding to TRAF2, and suggest how mutations of TRAF2, TRAF3 and cIAP1/cIAP2 may differentially contribute to B-lineage malignancies such as multiple myeloma.

Authors Gardam, S.; Turner, V.M.; Anderton, H.; Limaye, S.; Basten, A.; Koentgen, F.; Vaux, D.L.; Silke, J.; Brink, R.
Garvan Authors Prof Robert Brink
Publisher Name BLOOD
Published Date 2011-04-14 00:00:00
Published Volume 117
Published Issue 15
Published Pages 4041-51
URL http://www.ncbi.nlm.nih.gov/pubmed/21300983
Status Published In-print
OpenAccess Link https://publications.gimr.garvan.org.au/download.php?10351_11383/11.Gardam.Blood.pdf