BAFF selectively enhances the survival of plasmablasts generated from human memory B cells.
The generation of Ig-secreting cells (ISCs) from memory B cells requires interactions between antigen-specific (Ag-specific) B cells, T cells, and dendritic cells. This process must be strictly regulated to ensure sufficient humoral immunity while avoiding production of pathogenic autoantibodies. BAFF, a member of the TNF family, is a key regulator of B cell homeostasis. BAFF exerts its effect by binding to three receptors - transmembrane activator of and CAML interactor (TACI), B cell maturation antigen (BCMA), and BAFF receptor (BAFF-R). To elucidate the contribution of BAFF to the differentiation of B cells into ISCs, we tracked the fate of human memory B cells stimulated with BAFF or CD40L. BAFF and CD40L significantly increased the overall number of surviving B cells. This was achieved via distinct mechanisms. CD40L induced proliferation of nondifferentiated blasts, while BAFF prevented apoptosis of ISCs without enhancing proliferation. The altered responsiveness of activated memory B cells to CD40L and BAFF correlated with changes in surface phenotype such that expression of CD40 and BAFF-R were reduced on ISCs while BCMA was induced. These results suggest BAFF may enhance humoral immunity in vivo by promoting survival of ISCs via a BCMA-dependent mechanism. These findings have wide-ranging implications for the treatment of human immunodeficiencies as well as autoimmune diseases.
Avery
Danielle T
DT
Centenary Institute of Cancer Medicine and Cell Biology, Newton, Australia.
Kalled
Susan L
SL
Ellyard
Julia I
JI
Ambrose
Christine
C
Bixler
Sarah A
SA
Thien
Marilyn
M
Brink
Robert
R
Mackay
Fabienne
F
Hodgkin
Philip D
PD
Tangye
Stuart G
SG
D036541:ADP-ribosyl Cyclase / Q000096:biosynthesis; D051997:ADP-ribosyl Cyclase 1; D015703:Antigens, CD / Q000096:biosynthesis; D017209:Apoptosis; D053264:B-Cell Activating Factor; D053265:B-Cell Activation Factor Receptor; D053301:B-Cell Maturation Antigen; D001402:B-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D023201:CD40 Ligand / Q000378:metabolism; D002454:Cell Differentiation; D002455:Cell Division; D002460:Cell Line; D002469:Cell Separation; D002470:Cell Survival; D005434:Flow Cytometry; D006801:Humans; D007156:Immunologic Memory; D016753:Interleukin-10 / Q000096:biosynthesis; D007376:Interleukin-2 / Q000096:biosynthesis; D008562:Membrane Glycoproteins; D008565:Membrane Proteins / Q000378:metabolism / Q000502:physiology*; D008856:Microscopy, Fluorescence; D008954:Models, Biological; D009479:Neuropeptides / Q000502:physiology; D009687:Nuclear Proteins / Q000502:physiology; D011485:Protein Binding; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism; D013154:Spleen / Q000166:cytology; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism / Q000502:physiology*
C490341:ANP32B protein, human; D015703:Antigens, CD; D053264:B-Cell Activating Factor; D053265:B-Cell Activation Factor Receptor; D053301:B-Cell Maturation Antigen; D007376:Interleukin-2; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D009479:Neuropeptides; D009687:Nuclear Proteins; D018124:Receptors, Tumor Necrosis Factor; C435926:TNFRSF13C protein, human; C086966:TNFRSF17 protein, human; C505719:TNFSF13B protein, human; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D023201:CD40 Ligand; D036541:ADP-ribosyl Cyclase; C498154:CD38 protein, human; D051997:ADP-ribosyl Cyclase 1