Context-Specific BAFF-R Signaling by the NF-κB and PI3K Pathways
Julia Jellusova,
Ana V. Miletic,
Matthew H. Cato,
Wai-Wai Lin,
Yinling Hu,
Gail A. Bishop,
Mark J. Shlomchik,
Robert C. Rickert
Affiliations
Julia Jellusova
Program on Inflammatory Diseases, Infectious and Inflammatory Diseases Center, Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA
Ana V. Miletic
Program on Inflammatory Diseases, Infectious and Inflammatory Diseases Center, Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA
Matthew H. Cato
Program on Inflammatory Diseases, Infectious and Inflammatory Diseases Center, Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA
Wai-Wai Lin
Graduate Program in Immunology, The University of Iowa and the VA Medical Center, Iowa City, IA 52242, USA
Yinling Hu
Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD 21701, USA
Gail A. Bishop
Graduate Program in Immunology, The University of Iowa and the VA Medical Center, Iowa City, IA 52242, USA
Mark J. Shlomchik
Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA
Robert C. Rickert
Program on Inflammatory Diseases, Infectious and Inflammatory Diseases Center, Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA
BAFF is a soluble factor required for B cell maturation and survival. BAFF-R signals via the noncanonical NF-κB pathway regulated by the TRAF3/NIK/IKK1 axis. We show that deletion of Ikk1 during early B cell development causes a partial impairment in B cell maturation and BAFF-dependent survival, but inactivation of Ikk1 in mature B cells does not affect survival. We further show that BAFF-R employs CD19 to promote survival via phosphatidylinositol 3-kinase (PI3K), and that coinactivation of Cd19 and Ikk1 causes a profound block in B cell maturation at the transitional stage. Consistent with a role for PI3K in BAFF-R function, inactivation of PTEN mediates a partial rescue of B cell maturation and function in Baff−/− animals. Elevated PI3K signaling also circumvents BAFF-dependent survival in a spontaneous B cell lymphoma model. These findings indicate that the combined activities of PI3K and IKK1 drive peripheral B cell differentiation and survival in a context-dependent manner.
