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Germinal-center development of memory B cells driven by IL-9 from follicular helper T cells

Abstract

Germinal centers (GCs) support high-affinity, long-lived humoral immunity. How memory B cells develop in GCs is not clear. Through the use of a cell-cycle-reporting system, we identified GC-derived memory precursor cells (GC-MP cells) that had quit cycling and reached G0 phase while in the GC, exhibited memory-associated phenotypes with signs of affinity maturation and localized toward the GC border. After being transferred into adoptive hosts, GC-MP cells reconstituted a secondary response like genuine memory B cells. GC-MP cells expressed the interleukin 9 (IL-9) receptor and responded to IL-9. Acute treatment with IL-9 or antibody to IL-9 accelerated or retarded the positioning of GC-MP cells toward the GC edge and exit from the GC, and enhanced or inhibited the development of memory B cells, which required B cell–intrinsic responsiveness to IL-9. Follicular helper T cells (TFH cells) produced IL-9, and deletion of IL-9 from T cells or, more specifically, from GC TFH cells led to impaired memory formation of B cells. Therefore, the GC development of memory B cells is promoted by TFH cell–derived IL-9.

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Figure 1: Identification of G0-phase GC B cells that have undergone selection.
Figure 2: Post-selection G0 GC B cells are poised to leave the GC.
Figure 3: The exiting transitional mKO2hi GC B cells are precursors of GC memory cells.
Figure 4: IL-9 promotes the GC-to-memory transition.
Figure 5: IL-9 promotes the formation of memory B cells.
Figure 6: Intrinsic IL-9 responsiveness is required for the formation of memory B cells.
Figure 7: IL-9 produced by T cells is important for memory formation.
Figure 8: GC TFH cell–derived IL-9 promotes memory formation.

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Acknowledgements

We thank P. Schwartzberg (US National Institutes of Health) for the SAP-knockout mice; M. Nussenzweig (Rockefeller University) for the B1-8hi knock-in mice; and S. Crotty (La Jolla Institute of Allergy and Immunology) and Y.-C. Liu (Tsinghua University) for the MSCV-LMP vector. Supported by the Ministry of Science and Technology “973” program (2014CB542501), National Natural Science Foundation of China (81330070, 81425011, 81621002), the Tsinghua-Peking Center for Life Sciences and a Bayer endowed chair professorship (H.Q.).

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Y.W., J.S. and J.Y. contributed to the study design and conducted the majority of the experiments; Z.X. conducted informatics analyses under the supervision of X.Y., with contributions from J.S., S.H. and T.M.; X.H., Y.M. and L.Z. made the transgenic and knockout mice; P.L. and W.L. provided technical assistance; H.Q. designed and supervised the study and wrote the paper; and all authors contributed to data interpretation.

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Correspondence to Hai Qi.

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Wang, Y., Shi, J., Yan, J. et al. Germinal-center development of memory B cells driven by IL-9 from follicular helper T cells. Nat Immunol 18, 921–930 (2017). https://doi.org/10.1038/ni.3788

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