Limits...
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.

Show MeSH

Related in: MedlinePlus

BAFF-induced GC formation in the spleen and Ig deposition in the kidney require MALT1. (A) Spleen sections from mice of the indicated genotypes were immunostained to detect B220 plus the GC marker PNA (top) or B220 plus the MZ sinus marker MAdCAM-1 (bottom). Arrows indicate PNA+ GC B cells. (B) Kidney sections from the mice in A were stained with FITC-conjugated antibodies specific for the indicated Ig isotypes and visualized using fluorescence microscopy. Images shown are representative of four independent analyses of at least eight mice/genotype.
© Copyright Policy - openaccess
Related In: Results  -  Collection

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

fig7: BAFF-induced GC formation in the spleen and Ig deposition in the kidney require MALT1. (A) Spleen sections from mice of the indicated genotypes were immunostained to detect B220 plus the GC marker PNA (top) or B220 plus the MZ sinus marker MAdCAM-1 (bottom). Arrows indicate PNA+ GC B cells. (B) Kidney sections from the mice in A were stained with FITC-conjugated antibodies specific for the indicated Ig isotypes and visualized using fluorescence microscopy. Images shown are representative of four independent analyses of at least eight mice/genotype.

Mentions: BAFF-Tg mice exhibit a high frequency of PNA+ GC networks in the absence of immunization (Mackay et al., 1999), a phenomenon we also observed (Fig. 7 A, top). In contrast, no PNA+ cells were identified in sections of spleens from MALT1−/− × BAFF-Tg animals, indicating that the formation of BAFF-induced spontaneous GCs requires MALT1. Similar results were obtained for Bcl10−/− × BAFF-Tg mice. In addition, BAFF-Tg spleens (from either the WT or mixed bone marrow chimeric backgrounds) that were stained with MAdCAM-1 to delineate the MZ sinus showed that the MZ was increased in size (Fig. 7 A, bottom). This MZ expansion was not observed in MALT1−/− × BAFF-Tg or Bcl10−/− × BAFF-Tg mice. Similar results were obtained for MALT1−/− and Bcl10−/− mixed bone marrow chimeras, suggesting a B cell–intrinsic requirement for MALT1/Bcl10 for an expanded MZ (Fig. S6 B).


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)

BAFF-induced GC formation in the spleen and Ig deposition in the kidney require MALT1. (A) Spleen sections from mice of the indicated genotypes were immunostained to detect B220 plus the GC marker PNA (top) or B220 plus the MZ sinus marker MAdCAM-1 (bottom). Arrows indicate PNA+ GC B cells. (B) Kidney sections from the mice in A were stained with FITC-conjugated antibodies specific for the indicated Ig isotypes and visualized using fluorescence microscopy. Images shown are representative of four independent analyses of at least eight mice/genotype.
© Copyright Policy - openaccess
Related In: Results  -  Collection

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

fig7: BAFF-induced GC formation in the spleen and Ig deposition in the kidney require MALT1. (A) Spleen sections from mice of the indicated genotypes were immunostained to detect B220 plus the GC marker PNA (top) or B220 plus the MZ sinus marker MAdCAM-1 (bottom). Arrows indicate PNA+ GC B cells. (B) Kidney sections from the mice in A were stained with FITC-conjugated antibodies specific for the indicated Ig isotypes and visualized using fluorescence microscopy. Images shown are representative of four independent analyses of at least eight mice/genotype.
Mentions: BAFF-Tg mice exhibit a high frequency of PNA+ GC networks in the absence of immunization (Mackay et al., 1999), a phenomenon we also observed (Fig. 7 A, top). In contrast, no PNA+ cells were identified in sections of spleens from MALT1−/− × BAFF-Tg animals, indicating that the formation of BAFF-induced spontaneous GCs requires MALT1. Similar results were obtained for Bcl10−/− × BAFF-Tg mice. In addition, BAFF-Tg spleens (from either the WT or mixed bone marrow chimeric backgrounds) that were stained with MAdCAM-1 to delineate the MZ sinus showed that the MZ was increased in size (Fig. 7 A, bottom). This MZ expansion was not observed in MALT1−/− × BAFF-Tg or Bcl10−/− × BAFF-Tg mice. Similar results were obtained for MALT1−/− and Bcl10−/− mixed bone marrow chimeras, suggesting a B cell–intrinsic requirement for MALT1/Bcl10 for an expanded MZ (Fig. S6 B).

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