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Plasma cells negatively regulate the follicular helper T cell program

Nature Immunology volume 11, pages 1110–1118 (2010)Cite this article

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An Addendum to this article was published on 21 March 2011

Abstract

B lymphocytes differentiate into antibody-secreting cells under the antigen-specific control of follicular helper T cells (TFH cells). Here we demonstrate that isotype-switched plasma cells expressed major histocompatibility complex (MHC) class II, the costimulatory molecules CD80 and CD86, and the intracellular machinery required for antigen presentation. Antigen-specific plasma cells accessed, processed and presented sufficient antigen in vivo to induce multiple helper T cell functions. Notably, antigen-primed plasma cells failed to induce interleukin 21 (IL-21) or the transcriptional repressor Bcl-6 in naive helper T cells and actively decreased these key molecules in antigen-activated TFH cells. Mice lacking plasma cells showed altered TFH cell activity, which provided evidence of this negative feedback loop. Hence, antigen presentation by plasma cells defines a previously unknown layer of cognate regulation that limits the antigen-specific TFH cell program that controls ongoing B cell immunity.

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Figure 1: Isotype-switched plasma cells retain expression of MHCII and costimulatory molecules.
Figure 2: Plasma cells express the intracellular machinery for MHCII antigen processing and presentation.
Figure 3: Antigen-specific plasma cells process and present antigen in vivo.
Figure 4: Plasma cells induce proliferation, many helper T cell functions and Blimp-1 expression but not expression of Bcl-6 or IL-21.
Figure 5: Switched plasma cells selectively inhibit the expression of IL-21 and Bcl-6 in TFH cells.
Figure 6: More accumulation of TFH cells in the absence of plasma cells in vivo.
Figure 7: Plasma cells localize together with CD4+ T cells and negatively affect the antigen-specific TFH program in vivo.

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References

  1. MacLennan, I.C. Germinal centers. Annu. Rev. Immunol. 12, 117–139 (1994).

    Article  CAS  PubMed  Google Scholar 

  2. McHeyzer-Williams, L.J. & McHeyzer-Williams, M.G. Antigen-specific memory B cell development. Annu. Rev. Immunol. 23, 487–513 (2005).

    Article  CAS  PubMed  Google Scholar 

  3. Fazilleau, N., Mark, L., McHeyzer-Williams, L.J. & McHeyzer-Williams, M.G. Follicular helper T cells: lineage and location. Immunity 30, 324–335 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. King, C., Tangye, S.G. & Mackay, C.R. T follicular helper (TFH) cells in normal and dysregulated immune responses. Annu. Rev. Immunol. 26, 741–766 (2008).

    Article  CAS  PubMed  Google Scholar 

  5. Vinuesa, C.G., Sanz, I. & Cook, M.C. Dysregulation of germinal centres in autoimmune disease. Nat. Rev. Immunol. 9, 845–857 (2009).

    Article  CAS  PubMed  Google Scholar 

  6. Ansel, K.M., McHeyzer-Williams, L.J., Ngo, V.N., McHeyzer-Williams, M.G. & Cyster, J.G. In vivo-activated CD4 T cells upregulate CXC chemokine receptor 5 and reprogram their response to lymphoid chemokines. J. Exp. Med. 190, 1123–1134 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Fazilleau, N. et al. Lymphoid reservoirs of antigen-specific memory T helper cells. Nat. Immunol. 8, 753–761 (2007).

    Article  CAS  PubMed  Google Scholar 

  8. Fazilleau, N., McHeyzer-Williams, L.J., Rosen, H. & McHeyzer-Williams, M.G. The function of follicular helper T cells is regulated by the strength of T cell antigen receptor binding. Nat. Immunol. 10, 375–384 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Vinuesa, C.G., Tangye, S.G., Moser, B. & Mackay, C.R. Follicular B helper T cells in antibody responses and autoimmunity. Nat. Rev. Immunol. 5, 853–865 (2005).

    Article  CAS  PubMed  Google Scholar 

  10. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Poholek, A.C. et al. In vivo regulation of Bcl6 and T follicular helper cell development. J. Immunol. 185, 313–326 (2010).

    Article  CAS  PubMed  Google Scholar 

  13. Good-Jacobson, K.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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. McHeyzer-Williams, L.J., Cool, M. & McHeyzer-Williams, M.G. Antigen-specific B cell memory: expression and replenishment of a novel B220− memory B cell compartment. J. Exp. Med. 191, 1149–1166 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Banchereau, J. & Steinman, R.M. Dendritic cells and the control of immunity. Nature 392, 245–252 (1998).

    Article  CAS  PubMed  Google Scholar 

  16. Garside, P. et al. Visualization of specific B and T lymphocyte interactions in the lymph node. Science 281, 96–99 (1998).

    Article  CAS  PubMed  Google Scholar 

  17. Qi, H., Cannons, J.L., Klauschen, F., Schwartzberg, P.L. & Germain, R.N. SAP-controlled T-B cell interactions underlie germinal centre formation. Nature 455, 764–769 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Okada, T. et al. Antigen-engaged B cells undergo chemotaxis toward the T zone and form motile conjugates with helper T cells. PLoS Biol. 3, 1047–1061 (2005).

    Article  CAS  Google Scholar 

  19. Johnston, R.J. et al. Bcl6 and Blimp-1 are reciprocal and antagonistic regulators of T follicular helper cell differentiation. Science 325, 1006–1010 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Nurieva, R.I. et al. Bcl6 mediates the development of T follicular helper cells. Science 325, 1001–1005 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Yu, D. et al. The transcriptional repressor Bcl-6 directs T follicular helper cell lineage commitment. Immunity 31, 457–468 (2009).

    Article  CAS  PubMed  Google Scholar 

  22. Nurieva, R.I. et al. Generation of T follicular helper cells is mediated by interleukin-21 but independent of T helper 1, 2, or 17 cell lineages. Immunity 29, 138–149 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Vogelzang, A. et al. A fundamental role for interleukin-21 in the generation of T follicular helper cells. Immunity 29, 127–137 (2008).

    Article  CAS  PubMed  Google Scholar 

  24. Ozaki, K. et al. A critical role for IL-21 in regulating immunoglobulin production. Science 298, 1630–1634 (2002).

    Article  CAS  PubMed  Google Scholar 

  25. Spolski, R. & Leonard, W.J. The Yin and Yang of interleukin-21 in allergy, autoimmunity and cancer. Curr. Opin. Immunol. 20, 295–301 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Jacob, J. & Kelsoe, G. In situ studies of the primary immune response to (4-hydroxy-3-nitrophenyl)acetyl. II. A common clonal origin for periarteriolar lymphoid sheath-associated foci and germinal centers. J. Exp. Med. 176, 679–687 (1992).

    Article  CAS  PubMed  Google Scholar 

  27. McHeyzer-Williams, M.G., McLean, M.J., Lalor, P.A. & Nossal, G.J. Antigen-driven B cell differentiation in vivo. J. Exp. Med. 178, 295–307 (1993).

    Article  CAS  PubMed  Google Scholar 

  28. Ho, F., Lortan, J.E., MacLennan, I.C. & Khan, M. Distinct short-lived and long-lived antibody-producing cell populations. Eur. J. Immunol. 16, 1297–1301 (1986).

    Article  CAS  PubMed  Google Scholar 

  29. Slifka, M.K., Antia, R., Whitmire, J.K. & Ahmed, R. Humoral immunity due to long-lived plasma cells. Immunity 8, 363–372 (1998).

    Article  CAS  PubMed  Google Scholar 

  30. Shapiro-Shelef, M. et al. Blimp-1 is required for the formation of immunoglobulin secreting plasma cells and pre-plasma memory B cells. Immunity 19, 607–620 (2003).

    Article  CAS  PubMed  Google Scholar 

  31. Martins, G. & Calame, K. Regulation and functions of Blimp-1 in T and B lymphocytes. Annu. Rev. Immunol. 26, 133–169 (2008).

    Article  CAS  PubMed  Google Scholar 

  32. Reimold, A.M. et al. Plasma cell differentiation requires the transcription factor XBP-1. Nature 412, 300–307 (2001).

    Article  CAS  PubMed  Google Scholar 

  33. Todd, D.J. et al. XBP1 governs late events in plasma cell differentiation and is not required for antigen-specific memory B cell development. J. Exp. Med. 206, 2151–2159 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Ozaki, K. et al. Regulation of B cell differentiation and plasma cell generation by IL-21, a novel inducer of Blimp-1 and Bcl-6. J. Immunol. 173, 5361–5371 (2004).

    Article  CAS  PubMed  Google Scholar 

  35. Kwon, H. et al. Analysis of interleukin-21-induced Prdm1 gene regulation reveals functional cooperation of STAT3 and IRF4 transcription factors. Immunity 31, 941–952 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Piskurich, J.F. et al. BLIMP-I mediates extinction of major histocompatibility class II transactivator expression in plasma cells. Nat. Immunol. 1, 526–532 (2000).

    Article  CAS  PubMed  Google Scholar 

  37. McHeyzer-Williams, M.G., Nossal, G.J. & Lalor, P.A. Molecular characterization of single memory B cells. Nature 350, 502–505 (1991).

    Article  CAS  PubMed  Google Scholar 

  38. Dadaglio, G., Nelson, C.A., Deck, M.B., Petzold, S.J. & Unanue, E.R. Characterization and quantitation of peptide-MHC complexes produced from hen egg lysozyme using a monoclonal antibody. Immunity 6, 727–738 (1997).

    Article  CAS  PubMed  Google Scholar 

  39. Denzin, L.K., Fallas, J.L., Prendes, M. & Yi, W. Right place, right time, right peptide: DO keeps DM focused. Immunol. Rev. 207, 279–292 (2005).

    Article  CAS  PubMed  Google Scholar 

  40. Trombetta, E.S. & Mellman, I. Cell biology of antigen processing in vitro and in vivo. Annu. Rev. Immunol. 23, 975–1028 (2005).

    Article  CAS  PubMed  Google Scholar 

  41. Ellyard, J.I. et al. Antigen-selected, immunoglobulin-secreting cells persist in human spleen and bone marrow. Blood 103, 3805–3812 (2004).

    Article  CAS  PubMed  Google Scholar 

  42. Gonzalez-Garcia, I., Ocana, E., Jimenez-Gomez, G., Campos-Caro, A. & Brieva, J.A. Immunization-induced perturbation of human blood plasma cell pool: progressive maturation, IL-6 responsiveness, and high PRDI-BF1/BLIMP1 expression are critical distinctions between antigen-specific and nonspecific plasma cells. J. Immunol. 176, 4042–4050 (2006).

    Article  CAS  PubMed  Google Scholar 

  43. Yi, Q., Dabadghao, S., Osterborg, A., Bergenbrant, S. & Holm, G. Myeloma bone marrow plasma cells: evidence for their capacity as antigen-presenting cells. Blood 90, 1960–1967 (1997).

    CAS  PubMed  Google Scholar 

  44. Crotty, S., Johnston, R.J. & Schoenberger, S.P. Effectors and memories: Bcl-6 and Blimp-1 in T and B lymphocyte differentiation. Nat. Immunol. 11, 114–120 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. 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).

    Article  CAS  PubMed  Google Scholar 

  46. Reinhardt, R.L., Liang, H.E. & Locksley, R.M. Cytokine-secreting follicular T cells shape the antibody repertoire. Nat. Immunol. 10, 385–393 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Mohr, E. et al. Dendritic cells and monocyte/macrophages that create the IL-6/APRIL-rich lymph node microenvironments where plasmablasts mature. J. Immunol. 182, 2113–2123 (2009).

    Article  CAS  PubMed  Google Scholar 

  48. Angelin-Duclos, C., Cattoretti, G., Lin, K.I. & Calame, K. Commitment of B lymphocytes to a plasma cell fate is associated with Blimp-1 expression in vivo. J. Immunol. 165, 5462–5471 (2000).

    Article  CAS  PubMed  Google Scholar 

  49. Gatto, D., Paus, D., Basten, A., Mackay, C.R. & Brink, R. Guidance of B cells by the orphan G protein-coupled receptor EBI2 shapes humoral immune responses. Immunity 31, 259–269 (2009).

    Article  CAS  PubMed  Google Scholar 

  50. Yusuf, I. et al. Germinal center T follicular helper cell IL-4 production is dependent on signaling lymphocytic activation molecule receptor (CD150). J. Immunol. 185, 190–202 (2010).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank L. Denzin (Memorial Sloan Kettering Cancer Center) for antibodies 2C3A and Ob1; A. Rudensky (Memorial Sloan Kettering Cancer Center) for monoclonal antibody 15G4; E. Unanue (Washington University) for the Aw3.18 cell line; K. Calame (Columbia University) for mice with loxP-flanked Prdm1 alleles excised by Cre recombinase expressed from a CD19 promoter; and K. Spencer for help with confocal imaging. Supported by the German Academic Exchange Service (E.U.), the German Research Foundation (E.U.), the Canadian Institutes of Health Research (MFE-98574 to K.A.W.) and the US National Institutes of Health (AI047231, AI040215 and AI071182 to M.G.M.-W.). This is The Scripps Research Institute manuscript 20113.

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  1. Eduard Urich & Nicolas Fazilleau

    Present address: Present address: Roche, Basel, Switzerland (E.U.), and Institut National de la Santé et de la Recherche Médicale U563, Toulouse, France (N.F.).,

Authors and Affiliations

  1. Department of Immunology and Microbial Sciences, The Scripps Research Institute, La Jolla, California, USA

    Nadége Pelletier, Louise J McHeyzer-Williams, Kurt A Wong, Eduard Urich, Nicolas Fazilleau & Michael G McHeyzer-Williams

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Contributions

N.P., L.J.M.-W. and M.G.M.-W. conceived of and designed the project; N.P. provided and analyzed the data for all experiments except Figures 3a,b and 6; K.A.W. designed and completed the experiments and analyzed the data for pMHCII HEL-specific plasma cells (Fig. 3a,b); E.U. laid the experimental foundation for staining HEL-specific B cells; N.F. prepared the activated helper T cell samples for quantitative PCR analysis (Fig. 4b) and provided expertise in setting up the T cell in vitro experiments; L.J.M.-W. and M.G.M.-W. did the experiments for and analyzed the data from the Blimp-1-cKO mice (Fig. 6); K.A.W. and N.F. contributed ideas and participated in the manuscript preparation; and N.P., L.J.M.-W. and M.G.M.-W. wrote the manuscript.

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Correspondence to Michael G McHeyzer-Williams.

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Pelletier, N., McHeyzer-Williams, L., Wong, K. et al. Plasma cells negatively regulate the follicular helper T cell program. Nat Immunol 11, 1110–1118 (2010). https://doi.org/10.1038/ni.1954

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