Letter | Published:

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

Nature volume 501, pages 112115 (05 September 2013) | Download Citation

Abstract

The RAG1/RAG2 endonuclease (RAG) initiates the V(D)J recombination reaction that assembles immunoglobulin 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 specificity3,4,5. This ‘receptor editing’ process, which can also 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 postnatal B-cell development, the bone marrow is the principal location of primary immunoglobulin 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 immunoglobulin repertoires. At weanling age in normally housed mice, the LP contains a population of Rag-expressing B-lineage cells that harbour 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 repertoires, compared to those of Rag2-expressing bone marrow 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 extracellular signals from commensal microbes that influence gut immunoglobulin repertoires.

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Accessions

Gene Expression Omnibus

Data deposits

Microarray data have been deposited in MIAME format into the Gene Expression Omnibus GEO database under accession number GSE48870, and repertoire sequencing data have been deposited into the GEO database under accession number GSE48805.

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Acknowledgements

This work was supported by National Institutes of Health grants AI020047 (to F.W.A.) and AI89972 (to D.R.W.), Lymphoma and Leukemia SCOR 7009-12 (to F.W.A.), and National Institutes of Health research contract HHSN272201000053C (to T.B.K.). D.R.W. was also supported by an award from the American Academy of Allergy Asthma and Immunology and CSL-Behring and holds a Career Award for Medical Scientists from the Burroughs Wellcome Fund. F.W.A. is an Investigator of the Howard Hughes Medical Institute.

Author information

Affiliations

  1. Program in Cellular and Molecular Medicine and Department of Medicine, Children’s Hospital Boston, Boston, Massachusetts 02115, USA

    • Duane R. Wesemann
    • , Andrew J. Portuguese
    • , Robin M. Meyers
    • , Michael P. Gallagher
    • , Kendra Cluff-Jones
    • , Jennifer M. Magee
    • , Rohit A. Panchakshari
    •  & Frederick W. Alt
  2. Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA

    • Duane R. Wesemann
    • , Andrew J. Portuguese
    • , Robin M. Meyers
    • , Michael P. Gallagher
    • , Kendra Cluff-Jones
    • , Jennifer M. Magee
    • , Rohit A. Panchakshari
    •  & Frederick W. Alt
  3. Howard Hughes Medical Institute, Boston, Massachusetts 02115, USA

    • Duane R. Wesemann
    • , Andrew J. Portuguese
    • , Robin M. Meyers
    • , Michael P. Gallagher
    • , Kendra Cluff-Jones
    • , Jennifer M. Magee
    • , Rohit A. Panchakshari
    •  & Frederick W. Alt
  4. Division of Rheumatology, Immunology and Allergy, Department of Medicine, Brigham and Women’s Hospital, Boston, Massachusetts 02115, USA

    • Duane R. Wesemann
  5. Department of Pathology, Brigham and Women’s Hospital, Boston, Massachusetts 02115, USA

    • Scott J. Rodig
  6. Department of Microbiology, Boston University School of Medicine, Boston, Massachusetts 02215, USA

    • Thomas B. Kepler

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Contributions

D.R.W. and F.W.A. designed the study; D.R.W., A.J.P., M.P.G., K.C.-J., J.M.M. and R.A.P. performed experiments; R.M.M. and T.B.K. performed computational analysis of sequencing data; S.J.R. performed immunohistochemistry experiments; D.R.W. and F.W.A. wrote the paper.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Duane R. Wesemann or Frederick W. Alt.

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DOI

https://doi.org/10.1038/nature12496

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