Initiation of plasma-cell differentiation is independent of the transcription factor Blimp-1.
Blimp-1 is considered an essential regulator of the terminal differentiation of B cells into antibody-secreting plasma cells. We show here that Rag1-/- mice reconstituted with fetal liver cells homozygous for a DNA-binding-deficient mutant of Prdm1 (the gene encoding Blimp-1) lack a defined plasma-cell compartment, yet show detectable amounts of all immunoglobulin isotypes. In vitro analysis revealed that Blimp-1 is not required for the initiation of antibody secretion but is essential for subsequent high immunoglobulin production. Blimp-1-independent differentiation was blocked at a preplasmablast stage characterized by decreased Pax5 expression and the activation of plasma-cell genes. Analysis of Blimp-1-sufficient differentiation revealed a phase prior to Blimp-1 expression in which several genes normally repressed by Pax5 are re-expressed, suggesting that plasma-cell differentiation is initiated by the inhibition of Pax5 function. Our results indicate that full plasma-cell differentiation but not commitment to the plasma-cell fate requires the expression of functional Blimp-1.
Kallies
Axel
A
The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3050, Australia.
Hasbold
Jhagvaral
J
Fairfax
Kirsten
K
Pridans
Clare
C
Emslie
Dianne
D
McKenzie
Brent S
BS
Lew
Andrew M
AM
Corcoran
Lynn M
LM
Hodgkin
Philip D
PD
Tarlinton
David M
DM
Nutt
Stephen L
SL
D000818:Animals; D000906:Antibodies / Q000276:immunology; D000938:Antigen-Presenting Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D001402:B-Lymphocytes / Q000378:metabolism; D002454:Cell Differentiation / Q000276:immunology; D002478:Cells, Cultured; D004247:DNA / Q000378:metabolism; D005786:Gene Expression Regulation; D007074:Immunoglobulin G / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D051757:PAX5 Transcription Factor / Q000378:metabolism; D010950:Plasma Cells / Q000166:cytology* / Q000276:immunology / Q000378:metabolism*; D000074462:Positive Regulatory Domain I-Binding Factor 1; D011485:Protein Binding; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
D000906:Antibodies; D007074:Immunoglobulin G; D051757:PAX5 Transcription Factor; C497282:Pax5 protein, mouse; C513258:Prdm1 protein, mouse; D012097:Repressor Proteins; D014157:Transcription Factors; D004247:DNA; D000074462:Positive Regulatory Domain I-Binding Factor 1