Enhanced B cell expansion, survival, and humoral responses by targeting death receptor 6.
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 kappaB transcription factor, c-Rel, and elevated Bcl-x(l) 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.
Schmidt
Clint S
CS
Department of Bioresearch Technologies and Proteins, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, USA.
Liu
Jinqi
J
Zhang
Tonghai
T
Song
Ho Yeong
HY
Sandusky
George
G
Mintze
Karen
K
Benschop
Robert J
RJ
Glasebrook
Andrew
A
Yang
Derek D
DD
Na
Songqing
S
D000818:Animals; D017951:Antigen Presentation; D015703:Antigens, CD / Q000378:metabolism; D017209:Apoptosis; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D051940:B7-2 Antigen; D002455:Cell Division; D002470:Cell Survival; D002478:Cells, Cultured; D015536:Down-Regulation; D005434:Flow Cytometry; D017353:Gene Deletion; D007150:Immunohistochemistry; D008213:Lymphocyte Activation; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008934:Mitogens / Q000276:immunology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D020569:Proto-Oncogene Proteins c-rel / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D013601:T-Lymphocytes / Q000276:immunology; D015854:Up-Regulation; D051020:bcl-X Protein
D015703:Antigens, CD; D051940:B7-2 Antigen; C494812:Bcl2l1 protein, mouse; C497965:Cd86 protein, mouse; D008562:Membrane Glycoproteins; D008934:Mitogens; D019253:Proto-Oncogene Proteins c-bcl-2; D020569:Proto-Oncogene Proteins c-rel; D018124:Receptors, Tumor Necrosis Factor; C485251:Tnfrsf21 protein, mouse; D051020:bcl-X Protein