B cell receptor basal signaling regulates antigen-induced Ig light chain rearrangements.
BCR editing in the bone marrow contributes to B cell tolerance by orchestrating secondary Ig rearrangements in self-reactive B cells. We have recently shown that loss of the BCR or a pharmacologic blockade of BCR proximal signaling pathways results in a global "back-differentiation" response in which immature B cells down-regulate genes important for the mature B cell program and up-regulate genes characteristic of earlier stages of B cell development. These observations led us to test the hypothesis that self-Ag-induced down-regulation of the BCR, and not self-Ag-induced positive signals, lead to Rag induction and hence receptor editing. Supporting this hypothesis, we found that immature B cells from xid (x-linked immunodeficiency) mice induce re-expression of a Rag2-GFP bacterial artificial chromosome reporter as well as wild-type immature B cells following Ag incubation. Incubation of immature B cells with self-Ag leads to a striking reversal in differentiation to the pro-/pre-B stage of development, consistent with the idea that back-differentiation results in the reinduction of genes required for L chain rearrangement and receptor editing. Importantly, Rag induction, the back-differentiation response to Ag, and editing in immature and pre-B cells are inhibited by a combination of phorbol ester and calcium ionophore, agents that bypass proximal signaling pathways and mimic BCR signaling. Thus, mimicking positive BCR signals actually inhibits receptor editing. These findings support a model whereby Ag-induced receptor editing is inhibited by BCR basal signaling on developing B cells; BCR down-regulation removes this basal signal, thereby initiating receptor editing.
Schram
Brian R
BR
Center for Immunology, Department of Medicine, University of Minnesota Medical School, University of Minnesota, Minneapolis, MN 55455, USA.
Tze
Lina E
LE
Ramsey
Laura B
LB
Liu
Jiabin
J
Najera
Lydia
L
Vegoe
Amanda L
AL
Hardy
Richard R
RR
Hippen
Keli L
KL
Farrar
Michael A
MA
Behrens
Timothy W
TW
D000818:Animals; D000941:Antigens / Q000276:immunology*; D001402:B-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D015536:Down-Regulation / Q000276:immunology; D005260:Female; D017930:Genes, Reporter / Q000235:genetics; D006801:Humans; D007147:Immunoglobulin Light Chains / Q000276:immunology*; D007476:Ionophores / Q000494:pharmacology; D007700:Kinetics; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D020411:Oligonucleotide Array Sequence Analysis; D010703:Phorbol Esters / Q000494:pharmacology; D011947:Receptors, Antigen, B-Cell / Q000276:immunology*; D011961:Receptors, Fc / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology*; D019061:src-Family Kinases / Q000235:genetics / Q000378:metabolism
D000941:Antigens; D004268:DNA-Binding Proteins; D007147:Immunoglobulin Light Chains; D007476:Ionophores; D010703:Phorbol Esters; C499308:Rag2 protein, mouse; D011947:Receptors, Antigen, B-Cell; D011961:Receptors, Fc; C035311:immunoglobulin M receptor; C060902:lyn protein-tyrosine kinase; D019061:src-Family Kinases