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* Center for Immunology, Department of Medicine, University of Minnesota Medical School and
Center for Immunology, Department of Lab Medicine and Pathology, University of Minnesota, Minneapolis, MN 55455;
Institute for Cancer Research, Fox Chase Cancer Center, Philadelphia, PA 19111; and
Immunology, Tissue Growth and Repair, Exploratory Clinical Development, Genentech, Inc., San Francisco, CA 94080
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.
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1 This work was supported by grants from the National Institutes of Health.
2 B.R.S., L.E.T., and L.B.R. contributed equally to this work.
3 Current address: Division of Immunology and Genetics, The John Curtin School of Medical Research, Australian National University, Canberra, ACT 2601, Australia.
4 Address correspondence and reprint requests to Dr. Michael A. Farrar, Univeristy of Minnesota, 312 Church Street Southeast, Nils Hasselmo Hall, Room 6-116, Minneapolis, MN 55455. E-mail address: farra005{at}umn.edu
5 Abbreviations used in this paper: BM, bone marrow; Ctrl, control; DEL, duck egg lysozyme; Fr. D, fraction D; Fr. E, fraction E; hCk, human C
(constant region); HA, herbimycin A; HEL, hen egg lysozyme; hi (superscript), high; lo (superscript), low; mHEL, membrane-bound HEL; neg (superscript), negative; PP2, 4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine; sIg, surface Ig; Tg, transgenic; WT, wild type; XID, x-linked immunodeficiency.
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