Journal
JOURNAL OF IMMUNOLOGY
Volume 177, Issue 2, Pages 1120-1128Publisher
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.177.2.1120
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Funding
- NHLBI NIH HHS [T32 HL 07195] Funding Source: Medline
- NIAID NIH HHS [R01 AI 29672, R01 AI033608, R01 AI 61167] Funding Source: Medline
- NIAMS NIH HHS [R01 AR 42242] Funding Source: Medline
- NIGMS NIH HHS [R01 GM044809, T34 GM 08303] Funding Source: Medline
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CDR3 regions containing two D segments, or containing the footprints of V-H replacement events, have been reported in both mice and humans. However, the 12-23 bp rule for V(D)J recombination predicts that D-D rearrangements, which would occur between 2 recombination signal sequences (RSSs) with 12-bp spacers, should be extremely disfavored, and the cryptic RSS used for V-H replacement is very inefficient. We have previously shown that newborn mice, which lack TdT due to the late onset of its expression, do not contain any CDR3 with D-D rearrangements. In the present study, we test our hypothesis that most D-D rearrangements are due to fortuitous matching of the second apparent D segment by TdT-introduced N nucleotides. We analyzed 518 sequences from adult MRL/lpr- and C57BL/6 TdT-deficient B cell precursors and found only two examples of CDR3 with D-D rearrangements and one example of a potential V-H replacement event. We examined rearrangements from pre-B cells, marginal zone B cells, and follicular B cells from mice congenic for the Lbw5 (Sle3/5) lupus susceptibility loci and from other strains of mice and found very few examples of CDR3 with D-D rearrangements. We assayed B progenitor cells, and cells enriched for receptor editing, for DNA breaks at the cryptic heptamer but such breaks were rare. We conclude that many examples of apparent D-D rearrangements in the mouse are likely due to N additions that fortuitously match short stretches of D genes and that D-D rearrangements and V, replacement are rare occurrences in the mouse.
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