BAFF receptor signaling aids the differentiation of immature B cells into transitional B cells following tonic BCR signaling.
BAFF is an important prosurvival cytokine for mature B cells. However, previous studies have shown that BAFFR is already expressed at the immature B cell stage, and that the prosurvival protein Bcl-2 does not completely complement the B cell defects resulting from the absence of BAFFR or BAFF. Thus, we hypothesized that BAFF also functions to aid the differentiation of nonautoreactive immature B cells into transitional B cells and to promote their positive selection. We found that BAFFR is expressed at higher levels on nonautoreactive than on autoreactive immature B cells and that its expression correlates with that of surface IgM and with tonic BCR signaling. Our data indicate that BAFFR signaling enhances the generation of transitional CD23(-) B cells in vitro by increasing cell survival. In vivo, however, BAFFR signaling is dispensable for the generation of CD23(-) transitional B cells in the bone marrow, but it is important for the development of transitional CD23(-) T1 B cells in the spleen. Additionally, we show that BAFF is essential for the differentiation of CD23(-) into CD23(+) transitional B cells both in vitro and in vivo through a mechanism distinct from that mediating cell survival, but requiring tonic BCR signaling. In summary, our data indicate that BAFFR and tonic BCR signals cooperate to enable nonautoreactive immature B cells to differentiate into transitional B cells and to be positively selected into the naive B cell repertoire.
Rowland
Sarah L
SL
Integrated Department of Immunology, National Jewish Health and University of Colorado Denver, Denver, CO 80206, USA.
Leahy
Katelyn F
KF
Halverson
Regina
R
Torres
Raul M
RM
Pelanda
Roberta
R
D000818:Animals; D053264:B-Cell Activating Factor / Q000276:immunology / Q000378:metabolism; D053265:B-Cell Activation Factor Receptor / Q000276:immunology* / Q000378:metabolism; D016175:B-Lymphocyte Subsets / Q000166:cytology* / Q000276:immunology / Q000378:metabolism; D002454:Cell Differentiation / Q000276:immunology*; D002469:Cell Separation; D005434:Flow Cytometry; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D020411:Oligonucleotide Array Sequence Analysis; D054448:Precursor Cells, B-Lymphoid / Q000166:cytology* / Q000276:immunology / Q000378:metabolism; D011947:Receptors, Antigen, B-Cell / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology*
D053264:B-Cell Activating Factor; D053265:B-Cell Activation Factor Receptor; D011947:Receptors, Antigen, B-Cell; C505720:Tnfsf13b protein, mouse