The RAG1/RAG2 endonuclease ("RAG") initiates the V(D)J
recombination reaction that assembles Ig heavy
(IgH) and light (IgL) chain variable
region exons from germline gene segments to generate primary antibody
repertoires1.
IgH V(D)J assembly occurs in progenitor (pro-) B cells
followed by that of IgL in precursor (pre-) B cells. Expression
of IgH μ and IgL (Igκ or Igλ) chains generates IgM,
which is expressed on immature B cells as the B cell antigen-binding receptor
("BCR"). Rag expression can continue in
immature B cells2, allowing
continued Igκ V(D)J recombination that replaces the
initial VκJκ exon with one that generates a new
specificity3–5. This “receptor
editing” process, which also can lead to Igλ
V(D)J recombination and expression3,6,7, provides a mechanism whereby antigen-encounter
at the Rag-expressing immature B cell stage helps shape
pre-immune BCR repertoires. As the major site of post-natal B cell development,
the bone marrow is the principal location of primary Ig
repertoire diversification in mice. Here, we report that early B cell
development also occurs within the mouse intestinal lamina propria (LP), where
the associated V(D)J recombination/receptor editing processes modulate primary
LP Ig repertoires. At weanling age in normally housed mice, the
LP contains a population of Rag-expressing B lineage cells that
harbor intermediates indicative of ongoing V(D)J recombination and which contain
cells with pro-B, pre-B, and editing phenotypes. Consistent with LP-specific
receptor editing, Rag-expressing LP B-lineage cells have
similar VH repertoires, but significantly different
Vκ repertoires, compared to those of
Rag2-expressing BM counterparts. Moreover, colonization of
germ-free mice leads to an increased ratio of
Igλ-expressing versus
Igκ-expressing B cells specifically in the LP. We
conclude that B cell development occurs in the intestinal mucosa, where it is
regulated by extra-cellular signals from commensal microbes that influence gut
Ig repertoires.
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