title: Differing Requirements for MALT1 Function in Peripheral B Cell Survival and Differentiation.
abstract: During a T cell-dependent immune response, formation of the germinal center (GC) is essential for the generation of high-affinity plasma cells and memory B cells. The canonical NF-κB pathway has been implicated in the initiation of GC reaction, and defects in this pathway have been linked to immune deficiencies. The paracaspase MALT1 plays an important role in regulating NF-κB activation upon triggering of Ag receptors. Although previous studies have reported that MALT1 deficiency abrogates the GC response, the relative contribution of B cells and T cells to the defective phenotype remains unclear. We used chimeric mouse models to demonstrate that MALT1 function is required in B cells for GC formation. This role is restricted to BCR signaling where MALT1 is critical for B cell proliferation and survival. Moreover, the proapoptotic signal transmitted in the absence of MALT1 is dominant to the prosurvival effects of T cell-derived stimuli. In addition to GC B cell differentiation, MALT1 is required for plasma cell differentiation, but not mitogenic responses. Lastly, we show that ectopic expression of Bcl-2 can partially rescue the GC phenotype in MALT1-deficient animals by prolonging the lifespan of BCR-activated B cells, but plasma cell differentiation and Ab production remain defective. Thus, our data uncover previously unappreciated aspects of MALT1 function in B cells and highlight its importance in humoral immunity.
authors.affiliation: Tumor Microenvironment and Cancer Immunology Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037.|Biomedical Sciences Graduate Program, University of California at San Diego, La Jolla, CA 92037.
authors.forename: Peishan
authors.initials: P
authors.lastname: Lee
authors.affiliation: Tumor Microenvironment and Cancer Immunology Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037.
authors.forename: Zilu
authors.initials: Z
authors.lastname: Zhu
authors.affiliation: Tumor Microenvironment and Cancer Immunology Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037.|Graduate School of Biomedical Sciences, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037; and.
authors.forename: Janna
authors.initials: J
authors.lastname: Hachmann
authors.affiliation: Division of Molecular Biology, Research Institute for Biomedical Sciences, Tokyo University of Science, Noda, Chiba 278-0022, Japan.
authors.forename: Takuya
authors.identifier: 0000-0002-4519-9151
authors.initials: T
authors.lastname: Nojima
authors.affiliation: Division of Molecular Biology, Research Institute for Biomedical Sciences, Tokyo University of Science, Noda, Chiba 278-0022, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Kitamura
authors.affiliation: Tumor Microenvironment and Cancer Immunology Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037.
authors.forename: Guy
authors.identifier: 0000-0002-7933-6732
authors.initials: G
authors.lastname: Salvesen
authors.affiliation: Tumor Microenvironment and Cancer Immunology Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037; robert@SBPdiscovery.org.
authors.forename: Robert C
authors.initials: RC
authors.lastname: Rickert
mesh_terms: D000818:Animals; D017209:Apoptosis; D001402:B-Lymphocytes / Q000166:cytology / Q000502:physiology*; D020169:Caspases / Q000502:physiology*; D002454:Cell Differentiation; D002470:Cell Survival; D018858:Germinal Center / Q000502:physiology; D008213:Lymphocyte Activation; D051379:Mice; D000074884:Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein; D016328:NF-kappa B / Q000502:physiology; D009363:Neoplasm Proteins / Q000502:physiology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000032:analysis; D011947:Receptors, Antigen, B-Cell / Q000502:physiology; D051020:bcl-X Protein / Q000032:analysis
chemical_list: C494812:Bcl2l1 protein, mouse; D016328:NF-kappa B; D009363:Neoplasm Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D011947:Receptors, Antigen, B-Cell; D051020:bcl-X Protein; D020169:Caspases; C498509:Malt1 protein, mouse; D000074884:Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein