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Invariant natural killer T cells direct B cell responses to cognate lipid antigen in an IL-21-dependent manner

Nature Immunology volume 13, pages 44–50 (2012)Cite this article

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Abstract

Mouse invariant natural killer T cells (iNKT cells) provide cognate and noncognate help for lipid and protein-specific B cells, respectively. However, the long-term outcome for B cells after cognate help is provided by iNKT cells is unknown at present. Here we found that cognate iNKT cell help resulted in a B cell differentiation program characterized by extrafollicular plasmablasts, germinal-center formation, affinity maturation and a robust primary immunoglobulin G (IgG) antibody response that was uniquely dependent on iNKT cell–derived interleukin 21 (IL-21). However, cognate help from iNKT cells did not generate an enhanced humoral memory response. Thus, cognate iNKT cell help for lipid-specific B cells induces a unique signature that is a hybrid of classic T cell–dependent and T cell–independent type 2 B cell responses.

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Figure 1: Stimulation of B cells with cognate antigen (lipid) or noncognate antigen (lipid plus protein) induces splenic extrafollicular foci.
Figure 2: Stimulation of B cells with cognate antigen (lipid) or noncognate antigen (lipid plus protein) leads to the development of splenic GCs.
Figure 3: Cognate and noncognate iNKT cell help induces antigen-specific antibody affinity maturation.
Figure 4: IL-21R signaling is required for cognate iNKT cell–mediated anti-NP responses.
Figure 5: IL-21 produced by iNKT cells is required for cognate lipid antigen help.
Figure 6: Only noncognate iNKT cell help induces antibody memory response after day 177 rechallenge.
Figure 7: Only noncognate iNKT cell help induces an antibody memory response after rechallenge on day 46.

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References

  1. MacLennan, I.C. et al. Extrafollicular antibody responses. Immunol. Rev. 194, 8–18 (2003).

    Article  CAS  PubMed  Google Scholar 

  2. Jacob, J., Kelsoe, G., Rajewsky, K. & Weiss, U. Intraclonal generation of antibody mutants in germinal centres. Nature 354, 389–392 (1991).

    Article  CAS  PubMed  Google Scholar 

  3. Leadbetter, E.A. et al. NK T cells provide lipid antigen-specific cognate help for B cells. Proc. Natl. Acad. Sci. USA 105, 8339–8344 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Barral, P. et al. B cell receptor-mediated uptake of CD1d-restricted antigen augments antibody responses by recruiting invariant NKT cell help in vivo. Proc. Natl. Acad. Sci. USA 105, 8345–8350 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Godfrey, D.I., MacDonald, H.R., Kronenberg, M., Smyth, M.J. & Van Kaer, L. NKT cells: what's in a name? Nat. Rev. Immunol. 4, 231–237 (2004).

    Article  CAS  PubMed  Google Scholar 

  6. Roark, J.H. et al. CD1.1 expression by mouse antigen-presenting cells and marginal zone B cells. J. Immunol. 160, 3121–3127 (1998).

    CAS  PubMed  Google Scholar 

  7. Mandal, M. et al. Tissue distribution, regulation and intracellular localization of murine CD1 molecules. Mol. Immunol. 35, 525–536 (1998).

    Article  CAS  PubMed  Google Scholar 

  8. Cohen, N.R., Garg, S. & Brenner, M.B. Antigen presentation by CD1 lipids, T cells, and NKT cells in microbial immunity. Adv. Immunol. 102, 1–94 (2009).

    Article  CAS  PubMed  Google Scholar 

  9. Bendelac, A., Matzinger, P., Seder, R.A., Paul, W.E. & Schwartz, R.H. Activation events during thymic selection. J. Exp. Med. 175, 731–742 (1992).

    Article  CAS  PubMed  Google Scholar 

  10. Uldrich, A.P. et al. NKT cell stimulation with glycolipid antigen in vivo: costimulation-dependent expansion, Bim-dependent contraction, and hyporesponsiveness to further antigenic challenge. J. Immunol. 175, 3092–3101 (2005).

    Article  CAS  PubMed  Google Scholar 

  11. Kumar, H., Belperron, A., Barthold, S.W. & Bockenstedt, L.K. Cutting edge: CD1d deficiency impairs murine host defense against the spirochete, Borrelia burgdorferi. J. Immunol. 165, 4797–4801 (2000).

    Article  CAS  PubMed  Google Scholar 

  12. Belperron, A.A., Dailey, C.M. & Bockenstedt, L.K. Infection-induced marginal zone B cell production of Borrelia hermsii-specific antibody is impaired in the absence of CD1d. J. Immunol. 174, 5681–5686 (2005).

    Article  CAS  PubMed  Google Scholar 

  13. Kobrynski, L.J., Sousa, A.O., Nahmias, A.J. & Lee, F.K. Cutting edge: antibody production to pneumococcal polysaccharides requires CD1 molecules and CD8+ T cells. J. Immunol. 174, 1787–1790 (2005).

    Article  CAS  PubMed  Google Scholar 

  14. Schofield, L. et al. CD1d-restricted immunoglobulin G formation to GPI-anchored antigens mediated by NKT cells. Science 283, 225–229 (1999).

    Article  CAS  PubMed  Google Scholar 

  15. Bialecki, E. et al. Role of marginal zone B lymphocytes in invariant NKT cell activation. J. Immunol. 182, 6105–6113 (2009).

    Article  CAS  PubMed  Google Scholar 

  16. Muppidi, J.R. et al. Cannabinoid receptor 2 positions and retains marginal zone B cells within the splenic marginal zone. J. Exp. Med. 208, 1941–1948 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Galli, G. et al. Invariant NKT cells sustain specific B cell responses and memory. Proc. Natl. Acad. Sci. USA 104, 3984–3989 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Devera, T.S., Shah, H.B., Lang, G.A. & Lang, M.L. Glycolipid-activated NKT cells support the induction of persistent plasma cell responses and antibody titers. Eur. J. Immunol. 38, 1001–1011 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  20. Herzenberg, L.A., Black, S.J. & Tokuhisa, T. Memory B cells at successive stages of differentiation. Affinity maturation and the role of IgD receptors. J. Exp. Med. 151, 1071–1087 (1980).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Breitfeld, D. et al. Follicular B helper T cells express CXC chemokine receptor 5, localize to B cell follicles, and support immunoglobulin production. J. Exp. Med. 192, 1545–1552 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Schaerli, P. et al. CXC chemokine receptor 5 expression defines follicular homing T cells with B cell helper function. J. Exp. Med. 192, 1553–1562 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. 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 

  24. Johnston, B., Kim, C.H., Soler, D., Emoto, M. & Butcher, E.C. Differential chemokine responses and homing patterns of murine TCRαβ NKT cell subsets. J. Immunol. 171, 2960–2969 (2003).

    Article  CAS  PubMed  Google Scholar 

  25. Coquet, J.M. et al. IL-21 is produced by NKT cells and modulates NKT cell activation and cytokine production. J. Immunol. 178, 2827–2834 (2007).

    Article  CAS  PubMed  Google Scholar 

  26. King, I.L., Mohrs, K. & Mohrs, M. A nonredundant role for IL-21 receptor signaling in plasma cell differentiation and protective type 2 immunity against gastrointestinal helminth infection. J. Immunol. 185, 6138–6145 (2010).

    Article  CAS  PubMed  Google Scholar 

  27. 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 

  28. 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 

  29. 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 

  30. Hayakawa, Y. et al. Differential regulation of Th1 and Th2 functions of NKT cells by CD28 and CD40 costimulatory pathways. J. Immunol. 166, 6012–6018 (2001).

    Article  CAS  PubMed  Google Scholar 

  31. Ridderstad, A. & Tarlinton, D.M. Kinetics of establishing the memory B cell population as revealed by CD38 expression. J. Immunol. 160, 4688–4695 (1998).

    CAS  PubMed  Google Scholar 

  32. Randall, K.L. et al. Dock8 mutations cripple B cell immunological synapses, germinal centers and long-lived antibody production. Nat. Immunol. 10, 1283–1291 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Vinuesa, C.G., Linterman, M.A., Goodnow, C.C. & Randall, K.L. T cells and follicular dendritic cells in germinal center B-cell formation and selection. Immunol. Rev. 237, 72–89 (2010).

    Article  CAS  PubMed  Google Scholar 

  34. 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 

  35. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Stetson, D.B. et al. Constitutive cytokine mRNAs mark natural killer (NK) and NK T cells poised for rapid effector function. J. Exp. Med. 198, 1069–1076 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Muppidi, J.R. et al. Cannabinoid receptor 2 positions and retains marginal zone B cells within the splenic marginal zone. J. Exp. Med. 208, 1941–1948 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Cyster, J.G. B cells on the front line. Nat. Immunol. 1, 9–10 (2000).

    Article  CAS  PubMed  Google Scholar 

  39. Lopes-Carvalho, T., Foote, J. & Kearney, J.F. Marginal zone B cells in lymphocyte activation and regulation. Curr. Opin. Immunol. 17, 244–250 (2005).

    Article  CAS  PubMed  Google Scholar 

  40. Shih, T.-A.Y., Roederer, M. & Nussenzweig, M.C. Role of antigen-receptor affinity in T cell-independent antibody responses in vivo. Nat. Immunol. 3, 399–406 (2002).

    Article  CAS  PubMed  Google Scholar 

  41. Bendelac, A., Hunziker, R.D. & Lantz, O. Increased interleukin 4 and immunoglobulin E production in transgenic mice overexpressing NK1 T cells. J. Exp. Med. 184, 1285–1293 (1996).

    Article  CAS  PubMed  Google Scholar 

  42. Cui, J. et al. Requirement for Vα14 NKT cells in IL-12-mediated rejection of tumors. Science 28, 1623–1626 (1997).

    Article  Google Scholar 

  43. Lam, KP., Kuhn, R. & Rajewsky, K. In vivo ablation of surface immunoglobulin on mature B cells by inducible gene targeting results in rapid cell death. Cell 90, 1073–1083 (1997).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  45. Eaton, S.M., Burns, E.M., Kusser, K., Randall, T.D. & Haynes, L. Age-related defects in CD4 T cell cognate helper function lead to reductions in humoral responses. J. Exp. Med. 200, 1613–1622 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We thank M. Nussenzweig (Rockefeller University) for B6.SJL B1-8hi mice; M. Exley (Dana Farber Cancer Institute) for C57BL/6 Vα14-transgenic mice and C57BL/6 Jα18-deficient mice; K. Rajewsky (Center for Blood Research) for B1-8f mice; M. Rincon (University of Vermont) for IL-21-deficient mice; and the US National Institutes of Health Tetramer Core for mouse CD1d-PBS57 tetramers and unloaded CD1d tetramers. Supported by the Trudeau Institute (E.A.L.), the US National Institutes of Health (AI028973-23 and AI063428-06 to M.B.B. and T32 A1049823-10 to I.L.K.), J. Bardrick (G.S.B.), the Royal Society (G.S.B.), The Wellcome Trust (084923/B/08/Z to G.S.B.) and the Medical Research Council (G.S.B.).

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Authors and Affiliations

  1. Trudeau Institute, Saranac Lake, New York, USA

    Irah L King, Anne Fortier, Michael Tighe, John Dibble, Markus Mohrs & Elizabeth A Leadbetter

  2. Division of Rheumatology, Brigham & Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA

    Gerald F M Watts & Michael B Brenner

  3. School of Biosciences, University of Birmingham, Edgbaston, Birmingham, UK

    Natacha Veerapen & Gurdyal S Besra

  4. Department of Laboratory Medicine, Yale University School of Medicine, New Haven, Connecticut, USA

    Ann M Haberman

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Contributions

I.L.K. designed and did experiments, analyzed data and edited the manuscript; A.F., M.T., J.D. and G.F.M.W. designed and did experiments; A.M.H. did experiments, edited the manuscript and provided technical advice; N.V. and G.S.B. synthesized and provided lipid antigens; M.M. and M.B.B. provided conceptual advice and E.A.L. initiated and directed the research, did experiments, analyzed the data and wrote the manuscript.

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Correspondence to Elizabeth A Leadbetter.

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King, I., Fortier, A., Tighe, M. et al. Invariant natural killer T cells direct B cell responses to cognate lipid antigen in an IL-21-dependent manner. Nat Immunol 13, 44–50 (2012). https://doi.org/10.1038/ni.2172

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