Mucosal or systemic microbiota exposures shape the B cell repertoire

Hai Li, Julien P. Limenitakis, Victor Greiff, Bahtiyar Yilmaz, Olivier Schären, Camilla Urbaniak, Mirjam Zünd, Melissa A. E. Lawson, Ian D. Young, Sandra Rupp, Mathias Heikenwälder, Kathy D. McCoy, Siegfried Hapfelmeier, Stephanie C. Ganal-Vonarburg () and Andrew J. Macpherson ()
Additional contact information
Hai Li: University of Bern
Julien P. Limenitakis: University of Bern
Victor Greiff: University of Oslo
Bahtiyar Yilmaz: University of Bern
Olivier Schären: University of Bern
Camilla Urbaniak: McMaster University Medical Centre
Mirjam Zünd: University of Bern
Melissa A. E. Lawson: University of Bern
Ian D. Young: University of Bern
Sandra Rupp: University of Bern
Mathias Heikenwälder: German Cancer Research Center (DKFZ)
Kathy D. McCoy: University of Bern
Siegfried Hapfelmeier: University of Bern
Stephanie C. Ganal-Vonarburg: University of Bern
Andrew J. Macpherson: University of Bern

Nature, 2020, vol. 584, issue 7820, 274-278

Abstract: Abstract Colonization by the microbiota causes a marked stimulation of B cells and induction of immunoglobulin, but mammals colonized with many taxa have highly complex and individualized immunoglobulin repertoires1,2. Here we use a simplified model of defined transient exposures to different microbial taxa in germ-free mice3 to deconstruct how the microbiota shapes the B cell pool and its functional responsiveness. We followed the development of the immunoglobulin repertoire in B cell populations, as well as single cells by deep sequencing. Microbial exposures at the intestinal mucosa generated oligoclonal responses that differed from those of germ-free mice, and from the diverse repertoire that was generated after intravenous systemic exposure to microbiota. The IgA repertoire—predominantly to cell-surface antigens—did not expand after dose escalation, whereas increased systemic exposure broadened the IgG repertoire to both microbial cytoplasmic and cell-surface antigens. These microbial exposures induced characteristic immunoglobulin heavy-chain repertoires in B cells, mainly at memory and plasma cell stages. Whereas sequential systemic exposure to different microbial taxa diversified the IgG repertoire and facilitated alternative specific responses, sequential mucosal exposure produced limited overlapping repertoires and the attrition of initial IgA binding specificities. This shows a contrast between a flexible response to systemic exposure with the need to avoid fatal sepsis, and a restricted response to mucosal exposure that reflects the generic nature of host–microbial mutualism in the mucosa.

Date: 2020
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DOI: 10.1038/s41586-020-2564-6

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