Differing Requirements for MALT1 Function in Peripheral B Cell Survival and Differentiation [ANTIGEN RECOGNITION AND RESPONSES]

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.

This content is also available in: Español Português

Do NOT follow this link or you will be banned from the site!