1. Laboratory of Molecular Immunology, and,
2. Howard Hughes Medical Institute, The Rockefeller University, New York, New York 10021, USA
3. Program in Molecular Pathogenesis and Department of Pathology, Skirball Institute of Biomolecular Medicine, New York University School of Medicine, New York, New York 10016, USA
4. NovImmune SA, 64 avenue de la Roseraie, 1211 Geneva 4, Switzerland
5. Present address: Department of Immunology, Weizmann Institute of Science, Rehovot 76100, Israel.

Correspondence to: Michael L. Dustin³Michel C. Nussenzweig^1,2 Correspondence and requests for materials should be addressed to M.L.D. (Email: mikeroscope@nyc.rr.com) or M.C.N. (Email: nussen@rockefeller.edu).

Abstract

Germinal centres are specialized structures wherein B lymphocytes undergo clonal expansion, class switch recombination, antibody gene diversification and affinity maturation. Three to four antigen-specific B cells colonize a follicle to establish a germinal centre and become rapidly dividing germinal-centre centroblasts that give rise to dark zones^{1, 2, 3, 4}. Centroblasts produce non-proliferating centrocytes that are thought to migrate to the light zone of the germinal centre, which is rich in antigen-trapping follicular dendritic cells and CD4⁺ T cells^{5, 6, 7}. It has been proposed that centrocytes are selected in the light zone on the basis of their ability to bind cognate antigen^{5, 6, 7, 8}. However, there have been no studies of germinal-centre dynamics or the migratory behaviour of germinal-centre cells in vivo. Here we report the direct visualization of B cells in lymph node germinal centres by two-photon laser-scanning microscopy in mice. Nearly all antigen-specific B cells participating in a germinal-centre reaction were motile and physically restricted to the germinal centre but migrated bi-directionally between dark and light zones. Notably, follicular B cells were frequent visitors to the germinal-centre compartment, suggesting that all B cells scan antigen trapped in germinal centres. Consistent with this observation, we found that high-affinity antigen-specific B cells can be recruited to an ongoing germinal-centre reaction. We conclude that the open structure of germinal centres enhances competition and ensures that rare high-affinity B cells can participate in antibody responses.

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