Re-utilization of germinal centers in multiple Peyer's patches results in highly synchronized, oligoclonal, and affinity-matured gut IgA responses

P. Bergqvist, A. Stensson, L. Hazanov, A. Holmberg, J. Mattsson, R. Mehr, M. Bemark, N. Y. Lycke

Research output: Contribution to journalArticlepeer-review

81 Scopus citations

Abstract

Whereas gut IgA responses to the microbiota may be multi-centered and diverse, little is known about IgA responses to T-cell-dependent antigens following oral immunizations. Using a novel approach, gut IgA responses to oral hapten (4-hydroxy-3-nitrophenyl)acetyl-cholera toxin (NP-CT) conjugates were followed at the cellular and molecular level. Surprisingly, these responses were highly synchronized, strongly oligoclonal, and dominated by affinity matured cells. Extensive lineage trees revealed clonal relationships between NP-specific IgA cells in gut inductive and effector sites, suggesting expansion of the same B-cell clone in multiple Peyer's patches (PPs). Adoptive transfer experiments showed that this was achieved through re-utilization of already existing germinal centers (GCs) in multiple PPs by previously activated GC GL7 + B cells, provided oral NP-CT was given before cell transfer. Taken together, these results explain why repeated oral immunizations are mandatory for an effective oral vaccine.

Original languageEnglish
Pages (from-to)122-135
Number of pages14
JournalMucosal Immunology
Volume6
Issue number1
Early online date11 Jul 2012
DOIs
StatePublished - Jan 2013

Bibliographical note

Funding Information:
This study was supported by the Swedish Research Council, the Swedish Cancer Foundation, the Sahlgrenska University Hospital LUA / ALF grants, The Norwegian Research Council Globvac program, Israel Science Foundation 270 / 09, Human Frontiers Science Program Research Grant, and MIVAC Swedish Foundation for Strategic Research. We acknowledge the Centre for Cellular Imaging at the University of Gothenburg for skilled support and Michel C. Nussenzweig for generously providing the B1-8 high GFP mice. Finally, we would like to thank Dr Strober, NIH, for carefully reading the text and for helpful comments about the results and conclusions.

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