Editors' ChoiceImmunology

Microbiome-dependent recombination shapes the host antibody repertoire

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Sci. Signal.  21 Feb 2017:
Vol. 10, Issue 467, eaan0005
DOI: 10.1126/scisignal.aan0005

Secreted IgD concentration depends on the presence of microbiota.

Most immunoglobulin D (IgD) is produced as a transmembrane protein present on the surface of immature B cells. Infrequently, mature B cells produce a secreted form of IgD after undergoing a noncanonical form of class-switch recombination (CSR), a type of DNA recombination that changes the properties of the antibody produced from the gene. Choi et al. found that IgD class switching to produce the secreted form occurred in mucosal tissues and depended on the presence of commensal microbiota. A screen of a panel of mutant mice identified a strain homozygous for null mutations in a gene encoding the DNA damage–response protein 53BP1 (Trp53bp1–/–) that had a significantly higher concentration of serum IgD than did wild-type mice. The secreted IgD phenotype depended on the presence of functional activation–induced cytidine deaminase (AID), a DNA-editing enzyme involved in antibody diversification by CSR. Analysis of B cells from several mouse tissues for the recombination event that produces secreted IgD revealed that IgD CSR occurred mainly in mucosal-associated lymphoid tissues. IgD in serum from wild-type and Trp53bp1–/–mice bound to intestinal bacteria isolated from a mouse strain that produces no IgD or IgM, suggesting that secreted IgD may recognize host-associated bacteria. When Trp53bp1–/– mice were treated with broad-spectrum antibiotics, reducing but not completely eliminating intestinal bacteria, serum IgD concentration decreased. However, the composition of the intestinal microbiota was not significantly different between wild-type and Trp53bp1–/– mice, suggesting that the amount of secreted IgD did not alter the bacterial species present in the host. Conventionally raised mice with undisturbed microbiota (CNV) that received bone marrow from Trp53bp1–/– mice exhibited increased circulating IgD; whereas germ-free (GF) recipient mice did not, confirming that IgD secretion depended on the presence of microbiota. Furthermore, in wild-type mouse nasal-associated lymphoid tissue, both the presence of IgD CSR and the number of IgD+IgM cells depended on presence of microbiota because IgD CSR was undetectable in GF wild-type mice. This study reveals a mechanism by which nonpathogenic bacteria influence recombination in host cells and shape the host immune system and provides an example of how both wild-type and mutant animal phenotypes depend on the microbiome.

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