Microbial Influence in the Shaping of the Primary Immunoglobulin Repertoire

The pre-immune Ig repertoire is generated in developing bone marrow B cells through V(D)J recombination, resulting in production of IgM—first expressed on the surface of immature B cells as the antigen binding B cell receptor (BCR). Antigen encounter then provides Ig repertoire-shaping influences on developing naïve B cells through BCR receptor editing, clonal deletion, anergy, and cell fate determination. While it is known that self-antigens play a role in influencing the naïve Ig repertoire, the role of environmental antigens is not understood. In light of our previous work showing that primary B cell development—including V(D)J recombination and BCR editing—occurs in the gut lamina propria (LP) of weanling mice, we hypothesized that gut luminal antigens influence naïve B cell Ig repertoires. Using an assay we developed to test IgM-dependent B cell binding to small intestinal luminal content (sILC), we find that B cells from germ-free mice do not demonstrate detectable IgM-dependent sILC reactivity. However, naïve B cells from littermates exposed to conventional microbiota results in the appearance of IgM-dependent sILC reactivity into the naïve B cell repertoire. In contrast, B cells from both groups show no IgM-dependent reactivity to germ-free sILC. In addition, intravital microscopy reveals model luminal antigen in contact with naïve LP lymphocytes in the gut mucosa of weanling mice. These results suggest that non-pathogenic commensal/mutualistic microbes may benefit their hosts by providing antigenic substrates to naïve mucosal B cells, that serve as selection forces resulting in the injection anti-microbial specificities into the primary Ig repertoire.