[Show abstract][Hide abstract] 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.
Journal of Experimental Medicine 11/2009; 206(12):2671-83. · 13.21 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Germinal center (GC) responses to T-dependent Ags require effective collaboration between Th cells, activated B cells, and follicular dendritic cells within a highly organized microenvironment. Studies using gene-targeted mice have highlighted nonredundant molecules that are key for initiating and maintaining the GC niche, including the molecules of the ICOS, CD40, and lymphotoxin (LT) pathways. Signaling through ICOS has multiple consequences, including cytokine production, expression of CD40L on Th cells, and differentiation into CXCR5(+) follicular Th cells, all of which are important in the GC reaction. We have therefore taken advantage of ICOS(-/-) mice to dissect which downstream elements are required to initiate the formation of GC. In the context of a T-dependent immune response, we found that GC B cells from ICOS(-/-) mice express lower levels of LTalphabeta compared with wild-type GC B cells in vivo, and stimulation of ICOS on T cells induces LTalphabeta on B cells in vitro. Administration of agonistic anti-LTbeta receptor Ab was unable to restore the GC response in ICOS(-/-) mice, suggesting that additional input from another pathway is required for optimal GC generation. In contrast, treatment with agonistic anti-CD40 Ab in vivo recovered GC networks and restored LTalphabeta expression on GC B cells in ICOS(-/-) mice, and this effect was dependent on LTbeta receptor signaling. Collectively, these data demonstrate that ICOS activation is a prerequisite for the up-regulation of LTalphabeta on GC B cells in vivo and provide a model for cooperation between ICOS, CD40, and LT pathways in the context of the GC response.
The Journal of Immunology 03/2008; 180(4):2284-93. · 5.52 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The first studies of mice deficient in lymphotoxin-alpha (LTalpha), LTbeta and LTbetaR revealed the seminal discovery that the LTbetaR signaling is critical for the development of lymph nodes and Peyer's patches during embryogenesis. Since these initial findings, it is increasingly appreciated that signaling through the lymphotoxin-beta receptor (LTbetaR) plays a key role in numerous biological processes in the adult animal, including the maintenance of specialized stromal cell types and the homeostatic control of chemokine expression within the lymphoid tissues. A major focus of our laboratory is to understand the relevance of LTbetaR signaling in initiating immune responses both dependent and independent of its role in maintaining the organization of lymphoid tissues. This review will therefore explore new possibilities for how this complex pathway regulates humoral and cellular immunity.
Immunologic Research 02/2006; 35(1-2):41-54. · 2.96 Impact Factor