Cyclin D3 is selectively required for proliferative expansion of germinal center B cells.
The generation of robust T-cell-dependent humoral immune responses requires the formation and expansion of germinal center structures within the follicular regions of the secondary lymphoid tissues. B-cell proliferation in the germinal center drives ongoing antigen-dependent selection and the generation of high-affinity class-switched plasma and memory B cells. However, the mechanisms regulating B-cell proliferation within this microenvironment are largely unknown. Here, we report that cyclin D3 is uniquely required for germinal center progression. Ccnd3(-/-) mice exhibit a B-cell-intrinsic defect in germinal center maturation and fail to generate an affinity-matured IgG response. We determined that the defect resulted from failed proliferative expansion of GL7(+) IgD(-) PNA(+) B cells. Mechanistically, sustained expression of cyclin D3 was found to be regulated at the level of protein stability and controlled by glycogen synthase kinase 3 in a cyclic AMP-protein kinase A-dependent manner. The specific defect in proliferative expansion of GL7(+) IgD(-) PNA(+) B cells in Ccnd3(-/-) mice defines an underappreciated step in germinal center progression and solidifies a role for cyclin D3 in the immune response, and as a potential therapeutic target for germinal center-derived B-cell malignancies.
Program on Inflammatory Disease Research, Infectious and Inflammatory Disease Center, Sanford-Burnham Medical Research Institute, 10901 N. Torrey Pines Rd., La Jolla, CA 92037, USA.
Matthew H
MH
Cato
Suresh K
SK
Chintalapati
Irene W
IW
Yau
Sidne A
SA
Omori
Robert C
RC
Rickert
D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology* / Q000276:immunology* / Q000378:metabolism; D001483:Base Sequence; D002454:Cell Differentiation; D049109:Cell Proliferation; D056742:Cyclin D2 / Q000235:genetics / Q000276:immunology; D056743:Cyclin D3 / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D017931:DNA Primers / Q000235:genetics; D015870:Gene Expression; D018858:Germinal Center / Q000166:cytology* / Q000276:immunology* / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D007114:Immunization; D051379:Mice; D018345:Mice, Knockout; D018448:Models, Immunological; D015398:Signal Transduction; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology
C534697:Ccnd3 protein, mouse; D056742:Cyclin D2; D056743:Cyclin D3; D017931:DNA Primers; D038362:Glycogen Synthase Kinase 3