Microbial colonization influences early B-lineage development in the gut lamina propria

Abstract

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.

NKG2D Promotes B1a Cell Development and Protection against Bacterial Infection

“…B1a cells are predominantly formed during the perinatal period (42). At this stage, the gastrointestinal tract is colonized by commensal bacteria from food, resulting in an enormous boost of the mucosal immune system and shaping of the B cell compartment (43). To prevent opportunistic infection of the peritoneum, the innate B cell response must therefore limit bacterial expansion at this site (15).…”

The unfolded protein response, inflammation, oscillators, and disease: a systems biology approach

“…The net effect is the induction of B-cell tolerance to such resident microorganisms, and the increase of the repertoire of B-cell receptors [64].…”

Should We Be Treating the Bugs instead of Cytokines and T Cells?

“…Another study showed that short-chain fatty acids also regulate T reg and prevent T cell transfer colitis, possibly through similar mechanisms [35]. B cells are also affected by microbes as early development and recombination of immunoglobulin receptors on early B-lineage takes place in the gut lamina propria [36]. Although not directly related to gut immunity, microbes have also been shown to activate sensory neurons in the skin, leading directly to pain and inflammation [37].…”