Unexpected Rearrangement and Expression of the Immunoglobulin λ1 Locus in Scid Mice

Abstract

In severe combined immunodeficient (scid) mice, V(D)J recombination is severely impaired due to a recessive mutation (scid). Thus, we were surprised to find in this study that Vλ1–Jλ1 rearrangement is routinely detectable in scid fetal liver, adult bone marrow, and spleen in the apparent absence of completed VH–DJH and Vκ–Jκ rearrangements. Particularly surprising, we found the level of Vλ1–Jλ1 rearrangement in scid fetal liver to be comparable to that in fetal liver of wild-type mice. The majority of scid Vλ1–Jλ1 rearrangements contained abnormal deletions at the VJ junction, consistent with the known effect of scid. However, ∼15% of Vλ1–Jλ1 rearrangements lacked abnormal deletions. Productive λ1 transcripts resulting from in-frame rearrangements were readily detectable in scid adult bone marrow and spleen, consistent with our ability to detect λ1-expressing cells by flow cytometry in the spleens of bcl-2–transgenic scid mice. Strikingly, λ1 transcripts from individual scid mice often showed VJ junctional sequences with the same recurring palindromic (P) additions of three, four, or five nucleotides. To account for these findings, we suggest that (a) nonhomologous end joining of Vλ1 and Jλ1 coding ends in fetal B lineage cells may not be (severely) impaired by scid; (b) recurring P additions in scid λ1 transcripts may reflect certain molecular constraints imposed by scid on the resolution of Vλ1 and Jλ1 hairpin coding ends; and (c), scid lymphocytes with productively rearranged Vλ1 and Jλ1 elements may differentiate into recombinase-inactive cells and emigrate from bone marrow to spleen.