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A V_H12 Transgenic Mouse Exhibits Defects in Pre-B Cell Development and Is Unable to Make IgM⁺ B Cells¹

Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, NC 27599

V_H12 B cells undergo stringent selection at multiple checkpoints to favor development of B-1 cells that bind phosphatidylcholine. Selection begins with the V_H third complementarity-determining region (CDR3) at the pre-B cell stage, in which most V_H12 pre-B cells are selectively eliminated, enriching for those with V_HCDR3s of 10 aa and a fourth position Gly (designated 10/G4). To understand this selection, we compared B cell differentiation in mice of two V_H12 transgenic lines, one with the favored 10/G4 V_HCDR3 and one with a non-10/G4 V_HCDR3 of 8 aa and no Gly (8/G0). Both H chains drive B cell differentiation to the small pre-BII cell stage, and induce allelic exclusion and L chain gene rearrangement. However, unlike 10/G4 pre-B cells, 8/G0 pre-B cells are deficient in cell division and unable to differentiate to B cells. We suggest that this is due to poor 8/G0 pre-B cell receptor expression and to an inability to form an 8/G0 B cell receptor. Our findings also suggest that V_H12 H chains have evolved such that association with surrogate and conventional L chains is most efficient with a 10/G4 CDR3. Thus, selection for phosphatidylcholine-binding B-1 cells is most likely the underlying evolutionary basis for the loss of non-10/G4 pre-B cells.

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