Basal immunoglobulin signaling actively maintains developmental stage in immature B cells.
In developing B lymphocytes, a successful V(D)J heavy chain (HC) immunoglobulin (Ig) rearrangement establishes HC allelic exclusion and signals pro-B cells to advance in development to the pre-B stage. A subsequent functional light chain (LC) rearrangement then results in the surface expression of IgM at the immature B cell stage. Here we show that interruption of basal IgM signaling in immature B cells, either by the inducible deletion of surface Ig via Cre-mediated excision or by incubating cells with the tyrosine kinase inhibitor herbimycin A or the phosphatidylinositol 3-kinase inhibitor wortmannin, led to a striking "back-differentiation" of cells to an earlier stage in B cell development, characterized by the expression of pro-B cell genes. Cells undergoing this reversal in development also showed evidence of new LC gene rearrangements, suggesting an important role for basal Ig signaling in the maintenance of LC allelic exclusion. These studies identify a previously unappreciated level of plasticity in the B cell developmental program, and have important implications for our understanding of central tolerance mechanisms.
Tze
Lina E
LE
Center for Immunology, University of Minnesota Medical School, Minneapolis, Minnesota, USA.
Schram
Brian R
BR
Lam
Kong-Peng
KP
Hogquist
Kristin A
KA
Hippen
Keli L
KL
Liu
Jiabin
J
Shinton
Susan A
SA
Otipoby
Kevin L
KL
Rodine
Peter R
PR
Vegoe
Amanda L
AL
Kraus
Manfred
M
Hardy
Richard R
RR
Schlissel
Mark S
MS
Rajewsky
Klaus
K
Behrens
Timothy W
TW
D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D001854:Bone Marrow Cells / Q000166:cytology / Q000276:immunology; D002478:Cells, Cultured; D015321:Gene Rearrangement; D015322:Gene Rearrangement, B-Lymphocyte; D049452:Green Fluorescent Proteins / Q000235:genetics; D007143:Immunoglobulin Heavy Chains / Q000235:genetics; D007147:Immunoglobulin Light Chains / Q000235:genetics; D007075:Immunoglobulin M / Q000276:immunology; D007136:Immunoglobulins / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D015398:Signal Transduction / Q000276:immunology*; D000077191:Wortmannin
D000730:Androstadienes; D007143:Immunoglobulin Heavy Chains; D007147:Immunoglobulin Light Chains; D007075:Immunoglobulin M; D007136:Immunoglobulins; D049452:Green Fluorescent Proteins; D000077191:Wortmannin