Differential requirement for OBF-1 during antibody-secreting cell differentiation.
Resting B cells can be cultured to induce antibody-secreting cell (ASC) differentiation in vitro. A quantitative analysis of cell behavior during such a culture allows the influences of different stimuli and gene products to be measured. The application of this analytical system revealed that the OBF-1 transcriptional coactivator, whose loss impairs antibody production in vivo, has two effects on ASC development. Although OBF-1 represses early T cell-dependent (TD) differentiation, it is also critical for the completion of the final stages of ASC development. Under these conditions, the loss of OBF-1 blocks the genetic program of ASC differentiation so that Blimp-1/prdm1 induction fails, and bcl-6, Pax5, and AID are not repressed as in control ASC. Retroviral complementation confirmed that OBF-1 was the critical entity. Surprisingly, when cells were cultured in lipopolysaccharide to mimic T cell-independent conditions, OBF-1-null B cells differentiated normally to ASC. In the OBF-1(-/-) ASC generated under either culture regimen, antibody production was normal or only modestly reduced, revealing that Ig genes are not directly dependent on OBF-1 for their expression. The differential requirement for OBF-1 in TD ASC generation was confirmed in vivo. These studies define a new regulatory role for OBF-1 in determining the cell-autonomous capacity of B cells to undergo terminal differentiation in response to different immunological signals.
Corcoran
Lynn M
LM
The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3050, Australia. corcoran@wehi.edu.au
Hasbold
Jhagvaral
J
Dietrich
Wendy
W
Hawkins
Edwin
E
Kallies
Axel
A
Nutt
Stephen L
SL
Tarlinton
David M
DM
Matthias
Patrick
P
Hodgkin
Philip D
PD
D000818:Animals; D000921:Antibody-Producing Cells / Q000378:metabolism / Q000502:physiology*; D002454:Cell Differentiation / Q000502:physiology*; D002478:Cells, Cultured; D017931:DNA Primers; D004268:DNA-Binding Proteins / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D005786:Gene Expression Regulation; D005816:Genetic Complementation Test; D008070:Lipopolysaccharides; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051757:PAX5 Transcription Factor; D010950:Plasma Cells / Q000378:metabolism; D000074462:Positive Regulatory Domain I-Binding Factor 1; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051560:Proto-Oncogene Proteins c-bcl-6; D012097:Repressor Proteins / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015534:Trans-Activators / Q000378:metabolism / Q000502:physiology*; D014157:Transcription Factors / Q000378:metabolism
D017931:DNA Primers; D004268:DNA-Binding Proteins; D008070:Lipopolysaccharides; D051757:PAX5 Transcription Factor; C497282:Pax5 protein, mouse; C490424:Pou2af1 protein, mouse; C513258:Prdm1 protein, mouse; D011518:Proto-Oncogene Proteins; D051560:Proto-Oncogene Proteins c-bcl-6; D012097:Repressor Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D000074462:Positive Regulatory Domain I-Binding Factor 1