Enhanced B Cell Expansion, Survival, and Humoral Responses by Targeting Death Receptor 6

Abstract

Targeted disruption of death receptor (DR)6 results in enhanced CD4+ T cell expansion and T helper cell type 2 differentiation after stimulation. Similar to T cells, DR6 is expressed on resting B cells but is down-regulated upon activation. We examined DR6−/− B cell responses both in vitro and in vivo. In vitro, DR6−/− B cells undergo increased proliferation in response to anti–immunoglobulin M, anti-CD40, and lipopolysaccharide. This hyperproliferative response was due, at least in part, to both increased cell division and reduced cell apoptosis when compared with wild-type B cells. Consistent with these observations, increased nuclear levels and activity of nuclear factor κB transcription factor, c-Rel, and elevated Bcl-xl expression were observed in DR6−/− B cells upon stimulation. In addition, DR6−/− B cells exhibited higher surface levels of CD86 upon activation and were more effective as antigen-presenting cells in an allogeneic T cell proliferation response. DR6−/− mice exhibited enhanced germinal center formation and increased titers of immunoglobulins to T-dependent as well as T-independent type I and II antigens. This is the first demonstration of a regulatory role of DR6 in the activation and function of B cells.

Environmental Chemical-Induced Bone Marrow B Cell Apoptosis: Death Receptor-Independent Activation of a Caspase-3 to Caspase-8 Pathway

“…Primary bone marrow pro-B cell cultures were prepared from wild-type B6.129SF2/J and age-matched B6.129S6-Tnf tm1Gk1 /J (TNF-␣ Ϫ/Ϫ ) or B6.129S-Tnfrsf1a tm1Imx /Tnfrsf1b tm1Imx /J (TNFR1 Ϫ/Ϫ / TNFR2 Ϫ/Ϫ ) mice (The Jackson Laboratory, Bar Harbor, ME), wildtype BALB/c and age-matched BALB/c-lpr mice (the generous gifts of Dr. A. Marshak-Rothstein, Boston University School of Medicine, Boston, MA), B6.129-DR6 Ϫ/Ϫ mice and their wild-type littermates (Schmidt et al, 2003), or C57BL/6 mice essentially as described previously (Tze et al, 2000). Bone marrow was flushed from the femurs of 4-to 6-week-old male mice.…”

The c-Rel transcription factor and B-cell proliferation: a deal with the devil

“…Activation of c-Rel and B-cell proliferation/survival in response to B-cell receptor stimulation can be abolished by disruption of genes encoding the Syk (Harnett, 1996) and Bruton's tyrosine kinases (Kerner et al, 1995;Khan et al, 1995;Petro et al, 2000), the BLNK adaptor protein (Jumaa et al, 1999;Pappu et al, 1999;Hayashi et al, 2000;Tan et al, 2001), and phospholipase C-g2 (Wang et al, 2000;Petro and Khan, 2001), which are all involved in the PI3 kinase pathway. On the other hand, Death Receptor 6 may be a negative regulator of c-Rel function, in that mice with this gene knocked out have increased c-Rel activity in B cells and also have increased B-cell proliferation, survival, and germinal center formation (Schmidt et al, 2003). Not surprisingly, several c-Rel target genes in B cells are involved in growth, survival, proliferation, and antibody production (see Figure 1 and Table 1).…”

Historical perspectives on tumor necrosis factor and its superfamily: 25 years later, a golden journey

“…Enhanced CD4 ϩ T-cell expansion and Th2 differentiation; enhanced splenic GC formation 109 Impaired JNK activity; T-cell differentiation 110 CD4 ϩ T-cell proliferation; Th differentiation 111 …”