B cells expressing Bcl-2 and a signaling-impaired BAFF-specific receptor fail to mature and are deficient in the formation of lymphoid follicles and germinal centers.
The TNF family cytokine B cell-activating factor belonging to the TNF family (BAFF) (BLyS) plays a fundamental role in regulating peripheral B cell survival and homeostasis. A BAFF-specific receptor (BAFF-R; BR3) appears to mediate these functions via activation of the NF-kappaB2 pathway. Signaling by the BAFF-R is also required to sustain the germinal center (GC) reaction. Engagement of this receptor results in the induction of Bcl-2, suggesting that this antiapoptotic factor acts downstream of the BAFF-R and NF-kappaB2 pathway to promote peripheral B cell survival during primary and Ag-driven development. To test this idea, we created lines of mice coexpressing a Bcl-2 transgene and a signaling-deficient form of the BAFF-R derived from the B lymphopenic A/WySnJ strain. Surprisingly, although dramatically elevated numbers of B cells accumulate in the periphery of these mice, these B cells exhibit extremely perturbed primary development, formation of lymphoid microenvironments, and GC and IgG responses. Moreover, mice expressing the bcl-2 transgene alone display a loss of marginal zone B cells, an expansion of follicular B cells that appear immature, and alterations of the GC reaction. These results suggest that the BAFF-R and Bcl-2 regulate key and nonoverlapping aspects of peripheral B cell survival and development.
Rahman
Ziaur S M
ZS
Department of Microbiology and Immunology and The Kimmel Cancer Institute, Thomas Jefferson Medical College, Philadelphia, PA 19017, USA.
Manser
Tim
T
D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000276:immunology; D053264:B-Cell Activating Factor; D053265:B-Cell Activation Factor Receptor; D016175:B-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism* / Q000473:pathology*; D002449:Cell Aggregation / Q000235:genetics / Q000276:immunology; D016923:Cell Death / Q000235:genetics / Q000276:immunology; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D019070:Cell Lineage / Q000235:genetics / Q000276:immunology; D002645:Chickens; D018858:Germinal Center / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D007106:Immune Sera / Q000096:biosynthesis; D008221:Lymphoid Tissue / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D008231:Lymphopenia / Q000235:genetics / Q000276:immunology / Q000473:pathology; D008565:Membrane Proteins / Q000096:biosynthesis* / Q000378:metabolism* / Q000502:physiology; D051379:Mice; D008805:Mice, Inbred A; D008822:Mice, Transgenic; D009596:Nitrophenols / Q000276:immunology; D020033:Protein Isoforms / Q000096:biosynthesis; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology; D018124:Receptors, Tumor Necrosis Factor / Q000096:biosynthesis* / Q000502:physiology; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D013154:Spleen / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D013601:T-Lymphocytes / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D005719:gamma-Globulins / Q000096:biosynthesis
D053264:B-Cell Activating Factor; D053265:B-Cell Activation Factor Receptor; D007106:Immune Sera; D008565:Membrane Proteins; D009596:Nitrophenols; D020033:Protein Isoforms; D019253:Proto-Oncogene Proteins c-bcl-2; D018124:Receptors, Tumor Necrosis Factor; C486662:Tnfrsf13c protein, mouse; C505720:Tnfsf13b protein, mouse; D014409:Tumor Necrosis Factor-alpha; D005719:gamma-Globulins; C024836:4-nitrophenol