The Journal of Immunology, 2007,
178,
B39
Copyright © 2007 by The American Association of Immunologists, Inc.
Antigen-independent secondary Ig
rearrangement in B-cell development – implications for receptor editing
Feifei Liu1,2,
Lindsay G. Cowell3,
Emily Heikamp1 and
Garnett Kelsoe1
1 Department of Immunology, Duke University Medical Center, POBox 3010, Durham, NC, 27710,
2 Program in Cell and Molecular Biology, Duke University, POBox 3010, Durham, NC, 27710,
3 Department of Biostatistics and Bioinformatics, Duke University, Box 2734 Med Ctr, Durham, NC, 27710
Abstract
Receptor editing by secondary V
-to-J rearrangements is thought to be driven by reactivity to self. However, the evidence supporting antigen-driven editing is open to other interpretations; analysis of Ig excision circles from birds and mice indicates continuing V(D)J recombination in cis after both functional (F) and non-functional (nF) rearrangements. We have determined the extent and nature of secondary V-to-J rearrangements by analyzing their intermediate cleavage products in the 103/Bcl2 cell line and in purified compartments of developing B cells from normal, J–/+, and IgH transgenic mice. In all cases, we find that the ratio of F:nF VJ joints replaced by secondary rearrangement is approximately 1:2, the ratio expected for rearrangement without feedback of any kind. Secondary rearrangement is initiated in small pre-B cells and in BrdU pulse-labeling studies, we detected no evidence for immature to pre-B "retrograde" differentiation. Thus, "receptor editing" occurs in B cells that do not express surface Ig. Significantly, in 3H9 IgH transgenic mice, replacement rearrangements exhibited F:nF ratios of 1:2, regardless of whether the initial rearrangements were permissive or non-permissive for autoreactivity. Our results demonstrate continuing V-to-J rearrangement on a single chromosome without feedback and imply that "receptor editing" is an illusion of antigen-driven selection.
