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PD-1 regulates germinal center B cell survival and the formation and affinity of long-lived plasma cells

Nature Immunology volume 11, pages 535–542 (2010)Cite this article

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Abstract

Memory B and plasma cells (PCs) are generated in the germinal center (GC). Because follicular helper T cells (TFH cells) have high expression of the immunoinhibitory receptor PD-1, we investigated the role of PD-1 signaling in the humoral response. We found that the PD-1 ligands PD-L1 and PD-L2 were upregulated on GC B cells. Mice deficient in PD-L2 (Pdcd1lg2−/−), PD-L1 and PD-L2 (Cd274−/−Pdcd1lg2−/−) or PD-1 (Pdcd1−/−) had fewer long-lived PCs. The mechanism involved more GC cell death and less TFH cell cytokine production in the absence of PD-1; the effect was selective, as remaining PCs had greater affinity for antigen. PD-1 expression on T cells and PD-L2 expression on B cells controlled TFH cell and PC numbers. Thus, PD-1 regulates selection and survival in the GC, affecting the quantity and quality of long-lived PCs.

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Figure 1: Differences in the expression of PD-1 and its ligands by B cell subsets.
Figure 2: Long-lived PCs are lower in abundance in the absence of PD-1 signaling.
Figure 3: The decrease in PC numbers occurs during the late GC response and affects both IgG1 and IgM.
Figure 4: Greater cell death but normal proliferation in GCs of Pdcd1−/− mice.
Figure 5: More cells of a TFH phenotype correlates with lower cytokine production in the absence of PD-1 signaling.
Figure 6: The lower abundance of AFCs is due to impaired interactions between PD-ligands on B cells and PD-1 on T cells.
Figure 7: AFC production, memory B cell formation and TFH cells are altered in mixed–bone marrow chimeras.

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Acknowledgements

We thank K. Rajewsky (Harvard University) for B1-8 knock-in mice; T. Honjo (Kyoto University) for Pdcd1−/− mice; E. Song and G. Zuccarino-Catania for technical assistance; U. Hershberg for assistance in analyzing memory B cell sequencing data; the Yale Cell Sorter Facility for cell sorting; the Yale Animal Resource Center for animal care; the Craft and Haberman laboratories for oligonucleotides; and S. Kerfoot for critical reading of the manuscript. Supported by the National Institutes of Health (AI43603 to M.J.S., AI40614 to A.H.S. and K08AI78533 to M.M.T), the National Health and Medical Research Council (K.L.G.-J.) and Arthritis Australia (K.L.G.-J.).

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Authors and Affiliations

  1. Department of Laboratory Medicine and Department of Immunobiology, Yale University, New Haven, Connecticut, USA

    Kim L Good-Jacobson, Courtney G Szumilas & Mark J Shlomchik

  2. Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA

    Lieping Chen

  3. Department of Pathology, Harvard Medical School, Boston, Massachusetts, USA

    Arlene H Sharpe

  4. Department of Dermatology, Yale University, New Haven, Connecticut, USA

    Mary M Tomayko

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  1. Kim L Good-Jacobson
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Contributions

K.L.G.-J., M.M.T and M.J.S. designed research; K.L.G.-J. and C.G.S did research; L.C. and A.H.S. generated and contributed knockout mice; and K.L.G.-J. and M.J.S. analyzed data and wrote the manuscript.

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Correspondence to Mark J Shlomchik.

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Good-Jacobson, K., Szumilas, C., Chen, L. et al. PD-1 regulates germinal center B cell survival and the formation and affinity of long-lived plasma cells. Nat Immunol 11, 535–542 (2010). https://doi.org/10.1038/ni.1877

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