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.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Joshi, N.S. & Kaech, S.M. Effector CD8 T cell development: a balancing act between memory cell potential and terminal differentiation. J. Immunol. 180, 1309–1315 (2008).
Han, S. et al. Cellular interaction in germinal centers. Roles of CD40 ligand and B7–2 in established germinal centers. J. Immunol. 155, 556–567 (1995).
Jacob, J., Kelsoe, G., Rajewsky, K. & Weiss, U. Intraclonal generation of antibody mutants in germinal centres. Nature 354, 389–392 (1991).
Jacob, J., Przylepa, J., Miller, C. & Kelsoe, G. In situ studies of the primary immune response to (4-hydroxy-3-nitrophenyl)acetyl. III. The kinetics of V region mutation and selection in germinal center B cells. J. Exp. Med. 178, 1293–1307 (1993).
Takahashi, Y. et al. Relaxed negative selection in germinal centers and impaired affinity maturation in bcl-xL transgenic mice. J. Exp. Med. 190, 399–410 (1999).
Takahashi, Y., Dutta, P.R., Cerasoli, D.M. & Kelsoe, G. In situ studies of the primary immune response to (4-hydroxy-3-nitrophenyl)acetyl. V. Affinity maturation develops in two stages of clonal selection. J. Exp. Med. 187, 885–895 (1998).
Pasqualucci, L. et al. Hypermutation of multiple proto-oncogenes in B-cell diffuse large-cell lymphomas. Nature 412, 341–346 (2001).
Linterman, M.A. et al. Follicular helper T cells are required for systemic autoimmunity. J. Exp. Med. 206, 561–576 (2009).
Allen, R.C. et al. CD40 ligand gene defects responsible for X-linked hyper-IgM syndrome. Science 259, 990–993 (1993).
Klein, U. et al. Transcriptional analysis of the B cell germinal center reaction. Proc. Natl. Acad. Sci. USA 100, 2639–2644 (2003).
Tomayko, M.M. et al. Systematic comparison of gene expression between murine memory and naive B cells demonstrates that memory B cells have unique signaling capabilities. J. Immunol. 181, 27–38 (2008).
Good, K.L., Avery, D.T. & Tangye, S.G. Resting human memory B cells are intrinsically programmed for enhanced survival and responsiveness to diverse stimuli compared to naive B cells. J. Immunol. 182, 890–901 (2009).
Freeman, G.J. et al. Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation. J. Exp. Med. 192, 1027–1034 (2000).
Latchman, Y. et al. PD-L2 is a second ligand for PD-1 and inhibits T cell activation. Nat. Immunol. 2, 261–268 (2001).
Blackburn, S.D. et al. Coregulation of CD8+ T cell exhaustion by multiple inhibitory receptors during chronic viral infection. Nat. Immunol. 10, 29–37 (2009).
Butte, M.J., Keir, M.E., Phamduy, T.B., Sharpe, A.H. & Freeman, G.J. Programmed death-1 ligand 1 interacts specifically with the B7–1 costimulatory molecule to inhibit T cell responses. Immunity 27, 111–122 (2007).
Yamazaki, T. et al. Expression of programmed death 1 ligands by murine T cells and APC. J. Immunol. 169, 5538–5545 (2002).
Zhong, X., Tumang, J.R., Gao, W., Bai, C. & Rothstein, T.L. PD-L2 expression extends beyond dendritic cells/macrophages to B1 cells enriched for VH11/VH12 and phosphatidylcholine binding. Eur. J. Immunol. 37, 2405–2410 (2007).
Chtanova, T. et al. T follicular helper cells express a distinctive transcriptional profile, reflecting their role as non-Th1/Th2 effector cells that provide help for B cells. J. Immunol. 173, 68–78 (2004).
Allen, C.D., Okada, T., Tang, H.L. & Cyster, J.G. Imaging of germinal center selection events during affinity maturation. Science 315, 528–531 (2007).
Toellner, K.M., Gulbranson-Judge, A., Taylor, D.R., Sze, D.M. & MacLennan, I.C. Immunoglobulin switch transcript production in vivo related to the site and time of antigen-specific B cell activation. J. Exp. Med. 183, 2303–2312 (1996).
Liu, Y.J., Zhang, J., Lane, P.J., Chan, E.Y. & MacLennan, I.C. Sites of specific B cell activation in primary and secondary responses to T cell-dependent and T cell-independent antigens. Eur. J. Immunol. 21, 2951–2962 (1991).
Sharpe, A.H., Wherry, E.J., Ahmed, R. & Freeman, G.J. The function of programmed cell death 1 and its ligands in regulating autoimmunity and infection. Nat. Immunol. 8, 239–245 (2007).
Ha, S.J. et al. Enhancing therapeutic vaccination by blocking PD-1-mediated inhibitory signals during chronic infection. J. Exp. Med. 205, 543–555 (2008).
Anderson, S.M. et al. Taking advantage: high-affinity B cells in the germinal center have lower death rates, but similar rates of division, compared to low-affinity cells. J. Immunol. 183, 7314–7325 (2009).
Inamine, A. et al. Two waves of memory B-cell generation in the primary immune response. Int. Immunol. 17, 581–589 (2005).
Takahashi, Y., Ohta, H. & Takemori, T. Fas is required for clonal selection in germinal centers and the subsequent establishment of the memory B cell repertoire. Immunity 14, 181–192 (2001).
Hershberg, U., Uduman, M., Shlomchik, M.J. & Kleinstein, S.H. Improved methods for detecting selection by mutation analysis of Ig V region sequences. Int. Immunol. 20, 683–694 (2008).
Fazilleau, N., Mark, L., McHeyzer-Williams, L.J. & McHeyzer-Williams, M.G. Follicular helper T cells: lineage and location. Immunity 30, 324–335 (2009).
Sonoda, E. et al. B cell development under the condition of allelic inclusion. Immunity 6, 225–233 (1997).
Shlomchik, M.J., Zharhary, D., Saunders, T., Camper, S.A. & Weigert, M.G. A rheumatoid factor transgenic mouse model of autoantibody regulation. Int. Immunol. 5, 1329–1341 (1993).
Blink, E.J. et al. Early appearance of germinal center-derived memory B cells and plasma cells in blood after primary immunization. J. Exp. Med. 201, 545–554 (2005).
Ozaki, K. et al. A critical role for IL-21 in regulating immunoglobulin production. Science 298, 1630–1634 (2002).
Kinter, A.L. et al. The common γ-chain cytokines IL-2, IL-7, IL-15, and IL-21 induce the expression of programmed death-1 and its ligands. J. Immunol. 181, 6738–6746 (2008).
King, I.L. & Mohrs, M. IL-4-producing CD4+ T cells in reactive lymph nodes during helminth infection are T follicular helper cells. J. Exp. Med. 206, 1001–1007 (2009).
Zotos, D. et al. IL-21 regulates germinal center B cell differentiation and proliferation through a B cell-intrinsic mechanism. J. Exp. Med. 207, 365–378 (2010).
Linterman, M.A. et al. IL-21 acts directly on B cells to regulate Bcl-6 expression and germinal center responses. J. Exp. Med. 207, 353–363 (2010).
Avery, D.T. et al. B cell-intrinsic signaling through IL-21 receptor and STAT3 is required for establishing long-lived antibody responses in humans. J. Exp. Med. 207, 155–171 (2010).
Hasbold, J., Corcoran, L.M., Tarlinton, D.M., Tangye, S.G. & Hodgkin, P.D. Evidence from the generation of immunoglobulin G-secreting cells that stochastic mechanisms regulate lymphocyte differentiation. Nat. Immunol. 5, 55–63 (2004).
Hodgkin, P.D., Rush, J., Gett, A.V., Bartell, G. & Hasbold, J. The logic of intercellular communication in the immune system. Immunol. Cell Biol. 76, 448–453 (1998).
Francisco, L.M. et al. PD-L1 regulates the development, maintenance, and function of induced regulatory T cells. J. Exp. Med. 206, 3015–3029 (2009).
Shin, T. et al. Cooperative B7–1/2 (CD80/CD86) and B7-DC costimulation of CD4+ T cells independent of the PD-1 receptor. J. Exp. Med. 198, 31–38 (2003).
Keir, M.E. et al. Tissue expression of PD-L1 mediates peripheral T cell tolerance. J. Exp. Med. 203, 883–895 (2006).
Nishimura, H., Minato, N., Nakano, T. & Honjo, T. Immunological studies on PD-1 deficient mice: implication of PD-1 as a negative regulator for B cell responses. Int. Immunol. 10, 1563–1572 (1998).
Keir, M.E., Freeman, G.J. & Sharpe, A.H. PD-1 regulates self-reactive CD8+ T cell responses to antigen in lymph nodes and tissues. J. Immunol. 179, 5064–5070 (2007).
Hannum, L.G., Ni, D., Haberman, A.M., Weigert, M.G. & Shlomchik, M.J. A disease-related rheumatoid factor autoantibody is not tolerized in a normal mouse: implications for the origins of autoantibodies in autoimmune disease. J. Exp. Med. 184, 1269–1278 (1996).
Prak, E.L. & Weigert, M. Light chain replacement: a new model for antibody gene rearrangement. J. Exp. Med. 182, 541–548 (1995).
Chen, J. et al. Immunoglobulin gene rearrangement in B cell deficient mice generated by targeted deletion of the JH locus. Int. Immunol. 5, 647–656 (1993).
Hannum, L.G., Haberman, A.M., Anderson, S.M. & Shlomchik, M.J. Germinal center initiation, variable gene region hypermutation, and mutant B cell selection without detectable immune complexes on follicular dendritic cells. J. Exp. Med. 192, 931–942 (2000).
Anderson, S.M., Tomayko, M.M., Ahuja, A., Haberman, A.M. & Shlomchik, M.J. New markers for murine memory B cells that define mutated and unmutated subsets. J. Exp. Med. 204, 2103–2114 (2007).
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.).
Author information
Authors and Affiliations
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.
Corresponding author
Ethics declarations
Competing interests
The authors declare no competing financial interests.
Supplementary information
Supplementary Text and Figures
Supplementary Figures 1–3 (PDF 1617 kb)
Rights and permissions
About this article
Cite this article
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
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/ni.1877
This article is cited by
-
Polymer-mediated nanoformulations: a promising strategy for cancer immunotherapy
Naunyn-Schmiedeberg's Archives of Pharmacology (2024)
-
Helios characterized circulating follicular helper T cells with enhanced functional phenotypes and was increased in patients with systemic lupus erythematosus
Clinical and Experimental Medicine (2024)
-
Screening of prognosis-related Immune cells and prognostic predictors in Colorectal Cancer Patients
BMC Cancer (2023)
-
Antibodies against endogenous retroviruses promote lung cancer immunotherapy
Nature (2023)
-
Membrane tension sensing molecule-FNBP1 is a prognostic biomarker related to immune infiltration in BRCA, LUAD and STAD
BMC Immunology (2022)