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Differential requirement of MALT1 for BAFF-induced outcomes in B cell subsets.

Tusche MW, Ward LA, Vu F, McCarthy D, Quintela-Fandino M, Ruland J, Gommerman JL, Mak TW - J. Exp. Med. (2009)

Bottom Line: MALT1(-/-) MZ B cells also express higher amounts of TRAF3, a known negative regulator of BAFF receptor-mediated signaling, and TRAF3 was found to interact with MALT1.Furthermore, phenotypes associated with overexpression of BAFF, including increased MZ B cell numbers, elevated serum immunoglobulin titers, and spontaneous germinal center formation, were found to be dependent on B cell-intrinsic MALT1 expression.Our results demonstrate a novel role for MALT1 in biological outcomes induced by BAFF-mediated signal transduction.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Immunology, Faculty of Medicine, University of Toronto, Toronto, Ontario M5S 1A8, Canada.

ABSTRACT
B cell activation factor of the TNF family (BAFF) activates noncanonical nuclear factor kappaB (NF-kappaB) heterodimers that promote B cell survival. We show that although MALT1 is largely dispensable for canonical NF-kappaB signaling downstream of the B cell receptor, the absence of MALT1 results in impaired BAFF-induced phosphorylation of NF-kappaB2 (p100), p100 degradation, and RelB nuclear translocation in B220(+) B cells. This corresponds with impaired survival of MALT1(-/-) marginal zone (MZ) but not follicular B cells in response to BAFF stimulation in vitro. MALT1(-/-) MZ B cells also express higher amounts of TRAF3, a known negative regulator of BAFF receptor-mediated signaling, and TRAF3 was found to interact with MALT1. Furthermore, phenotypes associated with overexpression of BAFF, including increased MZ B cell numbers, elevated serum immunoglobulin titers, and spontaneous germinal center formation, were found to be dependent on B cell-intrinsic MALT1 expression. Our results demonstrate a novel role for MALT1 in biological outcomes induced by BAFF-mediated signal transduction.

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Td and Ti humoral responses are dysfunctional in the absence of MALT1. (A and B) Mice of the indicated genotypes (n = 4 mice/genotype) were left unimmunized (unim) or immunized (imm) with the Td antigen NP-CGG. GC B cells in the spleens of these mice were detected by immunostaining plus flow cytometry (percentages are shown). The quantification of the results of two such independent analyses are shown in B. Mice immunized with (C) the Td antigen NP-CGG or (D) the Ti antigen NP-Ficoll were analyzed by sandwich ELISA for the presence of low affinity (NP-30) and high affinity (NP-3) anti-NP antibodies. One out of two representative experiments is shown (n = 4 mice/genotype for each experiment). For B–D, white bars represent unimmunized controls and black bars represent immunized mice.
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fig6: Td and Ti humoral responses are dysfunctional in the absence of MALT1. (A and B) Mice of the indicated genotypes (n = 4 mice/genotype) were left unimmunized (unim) or immunized (imm) with the Td antigen NP-CGG. GC B cells in the spleens of these mice were detected by immunostaining plus flow cytometry (percentages are shown). The quantification of the results of two such independent analyses are shown in B. Mice immunized with (C) the Td antigen NP-CGG or (D) the Ti antigen NP-Ficoll were analyzed by sandwich ELISA for the presence of low affinity (NP-30) and high affinity (NP-3) anti-NP antibodies. One out of two representative experiments is shown (n = 4 mice/genotype for each experiment). For B–D, white bars represent unimmunized controls and black bars represent immunized mice.

Mentions: BAFF-R is required for optimal Td B cell responses, and Ti responses are augmented in BAFF-Tg mice (Schneider, 2005). To assess whether MALT1 is important for the effects of BAFF on Td responses, we immunized WT, MALT1−/−, and Bcl10−/− mice and their BAFF-Tg counterparts with the Td antigen NP–chicken γ-globulin (CGG). NP-CGG immunization induced a modest increase in the frequency of GC B cells (Fas+GL7+) in WT mice (Fig. 6, A and B). Numbers of GC B cells were already elevated in unimmunized BAFF-Tg mice, with a further increase observed when these mice were immunized (Fig. 6, A and B). However, even in the presence of excess BAFF antigen–specific B cell responses could not be mounted in the absence of MALT1, as judged by the frequency and numbers of total GC B cells (Fig. 6, A and B) and by measuring titers of low affinity (NP-30) and high affinity (NP-3) antibodies directed against NP-CGG (Fig. 6 C, left, top and bottom) or Ti antigen NP-Ficoll (Fig. 6 D). The same was true if MALT1 was absent exclusively in B cells in BAFF-Tg mice (Fig. S7). As expected, Bcl10−/− × BAFF-Tg mice also failed to mount a Td response in the presence or absence of the BAFF transgene (Fig. 6, A and B). Therefore, we observed that B cell–intrinsic expression of MALT1 is necessary to mount both Td and Ti response even in the presence of excess BAFF.


Differential requirement of MALT1 for BAFF-induced outcomes in B cell subsets.

Tusche MW, Ward LA, Vu F, McCarthy D, Quintela-Fandino M, Ruland J, Gommerman JL, Mak TW - J. Exp. Med. (2009)

Td and Ti humoral responses are dysfunctional in the absence of MALT1. (A and B) Mice of the indicated genotypes (n = 4 mice/genotype) were left unimmunized (unim) or immunized (imm) with the Td antigen NP-CGG. GC B cells in the spleens of these mice were detected by immunostaining plus flow cytometry (percentages are shown). The quantification of the results of two such independent analyses are shown in B. Mice immunized with (C) the Td antigen NP-CGG or (D) the Ti antigen NP-Ficoll were analyzed by sandwich ELISA for the presence of low affinity (NP-30) and high affinity (NP-3) anti-NP antibodies. One out of two representative experiments is shown (n = 4 mice/genotype for each experiment). For B–D, white bars represent unimmunized controls and black bars represent immunized mice.
© Copyright Policy - openaccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC2806610&req=5

fig6: Td and Ti humoral responses are dysfunctional in the absence of MALT1. (A and B) Mice of the indicated genotypes (n = 4 mice/genotype) were left unimmunized (unim) or immunized (imm) with the Td antigen NP-CGG. GC B cells in the spleens of these mice were detected by immunostaining plus flow cytometry (percentages are shown). The quantification of the results of two such independent analyses are shown in B. Mice immunized with (C) the Td antigen NP-CGG or (D) the Ti antigen NP-Ficoll were analyzed by sandwich ELISA for the presence of low affinity (NP-30) and high affinity (NP-3) anti-NP antibodies. One out of two representative experiments is shown (n = 4 mice/genotype for each experiment). For B–D, white bars represent unimmunized controls and black bars represent immunized mice.
Mentions: BAFF-R is required for optimal Td B cell responses, and Ti responses are augmented in BAFF-Tg mice (Schneider, 2005). To assess whether MALT1 is important for the effects of BAFF on Td responses, we immunized WT, MALT1−/−, and Bcl10−/− mice and their BAFF-Tg counterparts with the Td antigen NP–chicken γ-globulin (CGG). NP-CGG immunization induced a modest increase in the frequency of GC B cells (Fas+GL7+) in WT mice (Fig. 6, A and B). Numbers of GC B cells were already elevated in unimmunized BAFF-Tg mice, with a further increase observed when these mice were immunized (Fig. 6, A and B). However, even in the presence of excess BAFF antigen–specific B cell responses could not be mounted in the absence of MALT1, as judged by the frequency and numbers of total GC B cells (Fig. 6, A and B) and by measuring titers of low affinity (NP-30) and high affinity (NP-3) antibodies directed against NP-CGG (Fig. 6 C, left, top and bottom) or Ti antigen NP-Ficoll (Fig. 6 D). The same was true if MALT1 was absent exclusively in B cells in BAFF-Tg mice (Fig. S7). As expected, Bcl10−/− × BAFF-Tg mice also failed to mount a Td response in the presence or absence of the BAFF transgene (Fig. 6, A and B). Therefore, we observed that B cell–intrinsic expression of MALT1 is necessary to mount both Td and Ti response even in the presence of excess BAFF.

Bottom Line: MALT1(-/-) MZ B cells also express higher amounts of TRAF3, a known negative regulator of BAFF receptor-mediated signaling, and TRAF3 was found to interact with MALT1.Furthermore, phenotypes associated with overexpression of BAFF, including increased MZ B cell numbers, elevated serum immunoglobulin titers, and spontaneous germinal center formation, were found to be dependent on B cell-intrinsic MALT1 expression.Our results demonstrate a novel role for MALT1 in biological outcomes induced by BAFF-mediated signal transduction.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Immunology, Faculty of Medicine, University of Toronto, Toronto, Ontario M5S 1A8, Canada.

ABSTRACT
B cell activation factor of the TNF family (BAFF) activates noncanonical nuclear factor kappaB (NF-kappaB) heterodimers that promote B cell survival. We show that although MALT1 is largely dispensable for canonical NF-kappaB signaling downstream of the B cell receptor, the absence of MALT1 results in impaired BAFF-induced phosphorylation of NF-kappaB2 (p100), p100 degradation, and RelB nuclear translocation in B220(+) B cells. This corresponds with impaired survival of MALT1(-/-) marginal zone (MZ) but not follicular B cells in response to BAFF stimulation in vitro. MALT1(-/-) MZ B cells also express higher amounts of TRAF3, a known negative regulator of BAFF receptor-mediated signaling, and TRAF3 was found to interact with MALT1. Furthermore, phenotypes associated with overexpression of BAFF, including increased MZ B cell numbers, elevated serum immunoglobulin titers, and spontaneous germinal center formation, were found to be dependent on B cell-intrinsic MALT1 expression. Our results demonstrate a novel role for MALT1 in biological outcomes induced by BAFF-mediated signal transduction.

Show MeSH
Related in: MedlinePlus