Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

SAP-controlled T–B cell interactions underlie germinal centre formation

Nature volume 455, pages 764–769 (2008)Cite this article

Abstract

Generation of long-term antibody-mediated immunity depends on the germinal centre reaction, which requires cooperation between antigen-specific T and B lymphocytes. In human X-linked lymphoproliferative disease and its gene-targeted mouse model, loss-of-function mutations in signalling lymphocyte activation molecule-associated protein (SAP, encoded by SH2D1a) cause a profound defect in germinal centre formation by an as yet unknown mechanism. Here, using two-photon intravital imaging, we show that SAP deficiency selectively impairs the ability of CD4+ T cells to stably interact with cognate B cells but not antigen-presenting dendritic cells. This selective defect results in a failure of antigen-specific B cells to receive adequate levels of contact-dependent T-cell help to expand normally, despite Sap-/- T cells exhibiting the known characteristics of otherwise competent helper T cells. Furthermore, the lack of stable interactions with B cells renders Sap-/- T cells unable to be efficiently recruited to and retained in a nascent germinal centre to sustain the germinal centre reaction. These results offer an explanation for the germinal centre defect due to SAP deficiency and provide new insights into the bi-directional communication between cognate T and B cells in vivo.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Sap-/- T cells normally interact with and are activated by DCs in vivo.
Figure 2: Sap -/- T cells are defective in adhesion to cognate B cells.
Figure 3: B cells fail to receive contact-dependent help from SAP-deficient T cells.
Figure 4: Defective GC recruitment and retention of Sap -/- T cells due to lack of efficient cognate interactions with B cells.

Similar content being viewed by others

References

  1. Coico, R. F., Bhogal, B. S. & Thorbecke, G. J. Relationship of germinal centers in lymphoid tissue to immunologic memory. VI. Transfer of B cell memory with lymph node cells fractionated according to their receptors for peanut agglutinin. J. Immunol. 131, 2254–2257 (1983)

    CAS  PubMed  Google Scholar 

  2. Berek, C., Berger, A. & Apel, M. Maturation of the immune response in germinal centers. Cell 67, 1121–1129 (1991)

    Article  CAS  Google Scholar 

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

    Article  ADS  CAS  Google Scholar 

  4. MacLennan, I. C. et al. The changing preference of T and B cells for partners as T-dependent antibody responses develop. Immunol. Rev. 156, 53–66 (1997)

    Article  CAS  Google Scholar 

  5. Raff, M. C. Role of thymus-derived lymphocytes in the secondary humoral immune response in mice. Nature 226, 1257–1258 (1970)

    Article  ADS  CAS  Google Scholar 

  6. Mitchison, N. A. The carrier effect in the secondary response to hapten–protein conjugates. II. Cellular cooperation. Eur. J. Immunol. 1, 18–27 (1971)

    Article  CAS  Google Scholar 

  7. Lanzavecchia, A. Antigen-specific interaction between T and B cells. Nature 314, 537–539 (1985)

    Article  ADS  CAS  Google Scholar 

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

    Article  ADS  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  10. Purtilo, D. T., Cassel, C. K., Yang, J. P. & Harper, R. X-linked recessive progressive combined variable immunodeficiency (Duncan’s disease). Lancet 305, 935–940 (1975)

    Article  Google Scholar 

  11. Grierson, H. L. et al. Immunoglobulin class and subclass deficiencies prior to Epstein–Barr virus infection in males with X-linked lymphoproliferative disease. Am. J. Med. Genet. 40, 294–297 (1991)

    Article  CAS  Google Scholar 

  12. Ma, C. S., Nichols, K. E. & Tangye, S. G. Regulation of cellular and humoral immune responses by the SLAM and SAP families of molecules. Annu. Rev. Immunol. 25, 337–379 (2007)

    Article  CAS  Google Scholar 

  13. Wu, C. et al. SAP controls T cell responses to virus and terminal differentiation of TH2 cells. Nature Immunol. 2, 410–414 (2001)

    Article  CAS  Google Scholar 

  14. Czar, M. J. et al. Altered lymphocyte responses and cytokine production in mice deficient in the X-linked lymphoproliferative disease gene SH2D1A/DSHP/SAP . Proc. Natl Acad. Sci. USA 98, 7449–7454 (2001)

    Article  ADS  CAS  Google Scholar 

  15. Crotty, S. et al. SAP is required for generating long-term humoral immunity. Nature 421, 282–287 (2003)

    Article  ADS  CAS  Google Scholar 

  16. Morra, M. et al. Defective B cell responses in the absence of SH2D1A . Proc. Natl Acad. Sci. USA 102, 4819–4823 (2005)

    Article  ADS  CAS  Google Scholar 

  17. Cannons, J. L. et al. SAP regulates T cell-mediated help for humoral immunity by a mechanism distinct from cytokine regulation. J. Exp. Med. 203, 1551–1565 (2006)

    Article  CAS  Google Scholar 

  18. Coffey, A. J. et al. Host response to EBV infection in X-linked lymphoproliferative disease results from mutations in an SH2-domain encoding gene. Nature Genet. 20, 129–135 (1998)

    Article  CAS  Google Scholar 

  19. Sayos, J. et al. The X-linked lymphoproliferative-disease gene product SAP regulates signals induced through the co-receptor SLAM. Nature 395, 462–469 (1998)

    Article  ADS  CAS  Google Scholar 

  20. Cannons, J. L. et al. SAP regulates TH2 differentiation and PKC-θ-mediated activation of NF-κB1. Immunity 21, 693–706 (2004)

    Article  CAS  Google Scholar 

  21. Dent, A. L., Hu-Li, J., Paul, W. E. & Staudt, L. M. T helper type 2 inflammatory disease in the absence of interleukin 4 and transcription factor STAT6. Proc. Natl Acad. Sci. USA 95, 13823–13828 (1998)

    Article  ADS  CAS  Google Scholar 

  22. Andoh, A. et al. Absence of interleukin-4 enhances germinal center reaction in secondary immune response. Immunol. Lett. 73, 35–41 (2000)

    Article  CAS  Google Scholar 

  23. Huang, A. Y., Qi, H. & Germain, R. N. Illuminating the landscape of in vivo immunity: insights from dynamic in situ imaging of secondary lymphoid tissues. Immunity 21, 331–339 (2004)

    CAS  PubMed  Google Scholar 

  24. Stoll, S., Delon, J., Brotz, T. M. & Germain, R. N. Dynamic imaging of T cell–dendritic cell interactions in lymph nodes. Science 296, 1873–1876 (2002)

    Article  ADS  Google Scholar 

  25. Mempel, T. R., Henrickson, S. E. & Von Andrian, U. H. T-cell priming by dendritic cells in lymph nodes occurs in three distinct phases. Nature 427, 154–159 (2004)

    Article  ADS  CAS  Google Scholar 

  26. Miller, M. J., Safrina, O., Parker, I. & Cahalan, M. D. Imaging the single cell dynamics of CD4+ T cell activation by dendritic cells in lymph nodes. J. Exp. Med. 200, 847–856 (2004)

    Article  CAS  Google Scholar 

  27. Celli, S., Lemaitre, F. & Bousso, P. Real-time manipulation of T cell–dendritic cell interactions in vivo reveals the importance of prolonged contacts for CD4+ T cell activation. Immunity 27, 625–634 (2007)

    Article  CAS  Google Scholar 

  28. Abbas, A. K., Haber, S. & Rock, K. L. Antigen presentation by hapten-specific B lymphocytes. II. Specificity and properties of antigen-presenting B lymphocytes, and function of immunoglobulin receptors. J. Immunol. 135, 1661–1667 (1985)

    CAS  PubMed  Google Scholar 

  29. 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, e150 (2005)

    Article  Google Scholar 

  30. Davidson, D. et al. Genetic evidence linking SAP, the X-linked lymphoproliferative gene product, to Src-related kinase FynT in TH2 cytokine regulation. Immunity 21, 707–717 (2004)

    Article  CAS  Google Scholar 

  31. McCausland, M. M. et al. SAP regulation of follicular helper CD4 T cell development and humoral immunity is independent of SLAM and Fyn kinase. J. Immunol. 178, 817–828 (2007)

    Article  CAS  Google Scholar 

  32. Garcia, Z. et al. Competition for antigen determines the stability of T cell–dendritic cell interactions during clonal expansion. Proc. Natl Acad. Sci. USA 104, 4553–4558 (2007)

    Article  ADS  CAS  Google Scholar 

  33. Kelsoe, G. & Zheng, B. Sites of B-cell activation in vivo . Curr. Opin. Immunol. 5, 418–422 (1993)

    Article  CAS  Google Scholar 

  34. Liu, Y. J. et al. 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)

    Article  CAS  Google Scholar 

  35. Moser, B., Schaerli, P. & Loetscher, P. CXCR5+ T cells: follicular homing takes center stage in T-helper-cell responses. Trends Immunol. 23, 250–254 (2002)

    Article  CAS  Google Scholar 

  36. de Vinuesa, C. G. et al. Germinal centers without T cells. J. Exp. Med. 191, 485–494 (2000)

    Article  CAS  Google Scholar 

  37. Schwickert, T. A. et al. In vivo imaging of germinal centres reveals a dynamic open structure. Nature 446, 83–87 (2007)

    Article  ADS  CAS  Google Scholar 

  38. Al-Alwan, M. M., Rowden, G., Lee, T. D. & West, K. A. The dendritic cell cytoskeleton is critical for the formation of the immunological synapse. J. Immunol. 166, 1452–1456 (2001)

    Article  CAS  Google Scholar 

  39. Benvenuti, F. et al. Requirement of Rac1 and Rac2 expression by mature dendritic cells for T cell priming. Science 305, 1150–1153 (2004)

    Article  ADS  CAS  Google Scholar 

  40. 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)

    Article  CAS  Google Scholar 

  41. Hron, J. D. et al. SH2D1A regulates T-dependent humoral autoimmunity. J. Exp. Med. 200, 261–266 (2004)

    Article  CAS  Google Scholar 

  42. Crotty, S. et al. Hypogammaglobulinemia and exacerbated CD8 T-cell-mediated immunopathology in SAP-deficient mice with chronic LCMV infection mimics human XLP disease. Blood 108, 3085–3093 (2006)

    Article  CAS  Google Scholar 

  43. Ma, C. S. et al. Impaired humoral immunity in X-linked lymphoproliferative disease is associated with defective IL-10 production by CD4+ T cells. J. Clin. Invest. 115, 1049–1059 (2005)

    Article  CAS  Google Scholar 

  44. Qi, H., Egen, J. G., Huang, A. Y. & Germain, R. N. Extrafollicular activation of lymph node B cells by antigen-bearing dendritic cells. Science 312, 1672–1676 (2006)

    Article  ADS  CAS  Google Scholar 

Download references

Acknowledgements

H.Q. is in debt to Y. Hong for support, encouragement and inspiration. This work was funded by the intramural research programs of the National Institute of Allergy and Infectious Disease and National Human Genome Research Institute, National Institutes of Health, USA.

Author Contributions H.Q. and J.C. conducted the experiments. R.N.G. and P.L.S. contributed equally to this study. All authors contributed collectively to designing the experiments, interpreting the data and writing the paper.

Author information

Author notes

  1. Hai Qi and Jennifer L. Cannons: These authors contributed equally to this work.

Authors and Affiliations

  1. Lymphocyte Biology Section, Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA ,

    Hai Qi, Frederick Klauschen & Ronald N. Germain

  2. Genetic Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892, USA ,

    Jennifer L. Cannons & Pamela L. Schwartzberg

Authors
  1. Hai Qi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jennifer L. Cannons
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Frederick Klauschen
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Pamela L. Schwartzberg
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ronald N. Germain
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Pamela L. Schwartzberg or Ronald N. Germain.

Supplementary information

Supplementary Information 1

This files contains Supplementary Figures 1-10 with Legends and Supplementary Movie Legends 1-8 (PDF 18150 kb)

Supplementary Movie 1

Supplementary Movie 1, which shows sap+/+ and sap-/- T cell interactions with antigen-bearing DCs in the same lymph node. (MOV 2694 kb)

Supplementary Movie 2

Supplementary Movie 2, which shows sap+/+ and sap-/- T cell interactions with antigen-specific B cells in the same lymph node. (MOV 4422 kb)

Supplementary Movie 3

Supplementary Movie 3, which shows another example of sap+/+ and sap-/- T cell interactions with antigen-specific B cells in the same lymph node. (MOV 2852 kb)

Supplementary Movie 4

Supplementary Movie 4, which shows sap+/+ and sap-/- T cell interactions with antigen-specific B cells under non-competitive conditions. (MOV 10061 kb)

Supplementary Movie 5

Supplementary Movie 5, which shows examples of tracking B cells for their interaction histories with T cells. (MOV 11059 kb)

Supplementary Movie 6

Supplementary Movie 6, which shows further examples of tracking B cells for their interaction histories with T cells. (MOV 10038 kb)

Supplementary Movie 7

Supplementary Movie 7, which shows migration patterns of sap+/+ and sap-/- T cells within follicles containing non-cognate GCs. (QuickTime 9.0MB) (MOV 9244 kb)

Supplementary Movie 8

Supplementary Movie 8, which shows another example of migration patterns of sap+/+ and sap-/- T cells within follicles containing non-cognate GCs. (MOV 9621 kb)

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Cite this article

Qi, H., Cannons, J., Klauschen, F. et al. SAP-controlled T–B cell interactions underlie germinal centre formation. Nature 455, 764–769 (2008). https://doi.org/10.1038/nature07345

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature07345

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing