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.
Footnotes
-
This work was supported by National Institutes of Health Grants R01AI41649 (R.C.R.), R01GM099040 (G.S.), and F31CA165782 (P.L.).
-
The online version of this article contains supplemental material.
-
Abbreviations used in this article:
- 7-AAD
- 7-aminoactinomycin D
- ABC-DLBCL
- activated B cell-like diffuse large B cell lymphoma
- BM
- bone marrow
- Btk
- Bruton’s tyrosine kinase
- FO
- follicular
- GC
- germinal center
- iGB
- induced GC B cell
- KO
- knockout
- MZ
- marginal zone
- PKC
- protein kinase C
- PNA
- peanut agglutinin
- TD
- T dependent
- TFH,
- T FO helper
- TI
- T independent
- WT
- wild type.
- Received December 1, 2015.
- Accepted November 28, 2016.
- Copyright © 2017 by The American Association of Immunologists, Inc.