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Enhanced B Cell Expansion, Survival, and Humoral Responses by Targeting Death Receptor 6
Address correspondence to Songqing Na, Department of Bioresearch Technologies and Proteins, Lilly Corporate Center, Indianapolis, IN 46285. Phone: 317-277-6741; Fax: 317-277-2934; E-mail: na_songqing{at}lilly.com
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
B 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.
Key Words: hyperproliferation • TNFR superfamily • apoptosis • CD40 • spleen
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