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:

Interleukin 17–producing T helper cells and interleukin 17 orchestrate autoreactive germinal center development in autoimmune BXD2 mice

Nature Immunology volume 9, pages 166–175 (2008)Cite this article

Abstract

Interleukin 17 (IL-17) is a cytokine associated with inflammation, autoimmunity and defense against some bacteria. Here we show that IL-17 can promote autoimmune disease through a mechanism distinct from its proinflammatory effects. As compared with wild-type mice, autoimmune BXD2 mice express more IL-17 and show spontaneous development of germinal centers (GCs) before they increase production of pathogenic autoantibodies. We show that blocking IL-17 signaling disrupts CD4+ T cell and B cell interactions required for the formation of GCs and that mice lacking the IL-17 receptor have reduced GC B cell development and humoral responses. Production of IL-17 correlates with upregulated expression of the genes Rgs13 and Rgs16, which encode regulators of G-protein signaling, and results in suppression of the B cell chemotactic response to the chemokine CXCL12. These findings suggest a mechanism by which IL-17 drives autoimmune responses by promoting the formation of spontaneous GCs.

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: Enhanced development of TH-17 cells in BXD2 mice.
Figure 2: Formation of spontaneous GCs and localization of TH-17 cells and IL-17R+ B cells in the spleen.
Figure 3: IL-17 modifies chemotaxis and induces Rgs13 and Rgs16 expression in B cells.
Figure 4: Induction of GCs in vivo on administration of IL-17.
Figure 5: Disruption of GCs in BXD2 mice treated with AdIL-17R:Fc.
Figure 6: Reduced GC formation, Aicda expression and SHM in BXD2 Il17r−/− mice.
Figure 7: Defective generation of autoantibodies and autoantibody-producing B cells in the absence of IL-17R.

Similar content being viewed by others

References

  1. Kolls, J.K. & Linden, A. Interleukin-17 family members and inflammation. Immunity 21, 467–476 (2004).

    Article  CAS  Google Scholar 

  2. Lubberts, E., Koenders, M.I. & van den Berg, W.B. The role of T-cell interleukin-17 in conducting destructive arthritis: lessons from animal models. Arthritis Res. Ther. 7, 29–37 (2005).

    Article  CAS  Google Scholar 

  3. Raza, K. et al. Early rheumatoid arthritis is characterized by a distinct and transient synovial fluid cytokine profile of T cell and stromal cell origin. Arthritis Res. Ther. 7, R784–R795 (2005).

    Article  CAS  Google Scholar 

  4. Teunissen, M.B., Koomen, C.W., de Waal Malefyt, R., Wierenga, E.A. & Bos, J.D. Interleukin-17 and interferon-γ synergize in the enhancement of proinflammatory cytokine production by human keratinocytes. J. Invest. Dermatol. 111, 645–649 (1998).

    Article  CAS  Google Scholar 

  5. Harrington, L.E. et al. Interleukin 17-producing CD4+ effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages. Nat. Immunol. 6, 1123–1132 (2005).

    Article  CAS  Google Scholar 

  6. Mangan, P.R. et al. Transforming growth factor-β induces development of the TH17 lineage. Nature 441, 231–234 (2006).

    Article  CAS  Google Scholar 

  7. Park, H. et al. A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17. Nat. Immunol. 6, 1133–1141 (2005).

    Article  CAS  Google Scholar 

  8. Komiyama, Y. et al. IL-17 plays an important role in the development of experimental autoimmune encephalomyelitis. J. Immunol. 177, 566–573 (2006).

    Article  CAS  Google Scholar 

  9. Nakae, S., Nambu, A., Sudo, K. & Iwakura, Y. Suppression of immune induction of collagen-induced arthritis in IL-17–deficient mice. J. Immunol. 171, 6173–6177 (2003).

    Article  CAS  Google Scholar 

  10. Sonderegger, I. et al. Neutralization of IL-17 by active vaccination inhibits IL-23–dependent autoimmune myocarditis. Eur. J. Immunol. 36, 2849–2856 (2006).

    Article  CAS  Google Scholar 

  11. Taylor, B.A. et al. Genotyping new BXD recombinant inbred mouse strains and comparison of BXD and consensus maps. Mamm. Genome 10, 335–348 (1999).

    Article  CAS  Google Scholar 

  12. Mountz, J.D. et al. Genetic segregation of spontaneous erosive arthritis and generalized autoimmune disease in the BXD2 recombinant inbred strain of mice. Scand. J. Immunol. 61, 128–138 (2005).

    Article  CAS  Google Scholar 

  13. Wu, Y. et al. Synovial fibroblasts promote osteoclast formation by RANKL in a novel model of spontaneous erosive arthritis. Arthritis Rheum. 52, 3257–3268 (2005).

    Article  CAS  Google Scholar 

  14. Hsu, H.C. et al. Production of a novel class of polyreactive pathogenic autoantibodies in BXD2 mice causes glomerulonephritis and arthritis. Arthritis Rheum. 54, 343–355 (2006).

    Article  CAS  Google Scholar 

  15. Hsu, H.C. et al. Overexpression of activation-induced cytidine deaminase in B cells is associated with production of highly pathogenic autoantibodies. J. Immunol. 178, 5357–5365 (2007).

    Article  CAS  Google Scholar 

  16. Allen, C.D. et al. Germinal center dark and light zone organization is mediated by CXCR4 and CXCR5. Nat. Immunol. 5, 943–952 (2004).

    Article  CAS  Google Scholar 

  17. 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  Google Scholar 

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

    Article  CAS  Google Scholar 

  19. Walker, L.S. et al. Established T cell–driven germinal center B cell proliferation is independent of CD28 signaling but is tightly regulated through CTLA-4. J. Immunol. 170, 91–98 (2003).

    Article  CAS  Google Scholar 

  20. Cassese, G. et al. Inflamed kidneys of NZB/W mice are a major site for the homeostasis of plasma cells. Eur. J. Immunol. 31, 2726–2732 (2001).

    Article  CAS  Google Scholar 

  21. Luzina, I.G. et al. Spontaneous formation of germinal centers in autoimmune mice. J. Leukoc. Biol. 70, 578–584 (2001).

    CAS  PubMed  Google Scholar 

  22. Nordstrom, E., Abedi-Valugerdi, M. & Moller, E. Longevity of immune complexes and abnormal germinal centre formation in NZB mice. Scand. J. Immunol. 52, 477–482 (2000).

    Article  CAS  Google Scholar 

  23. Wang, Y. & Carter, R.H. CD19 regulates B cell maturation, proliferation, and positive selection in the FDC zone of murine splenic germinal centers. Immunity 22, 749–761 (2005).

    Article  CAS  Google Scholar 

  24. Berman, D.M., Wilkie, T.M. & Gilman, A.G. GAIP and RGS4 are GTPase-activating proteins for the Gi subfamily of G protein α subunits. Cell 86, 445–452 (1996).

    Article  CAS  Google Scholar 

  25. Koelle, M.R. A new family of G-protein regulators—the RGS proteins. Curr. Opin. Cell Biol. 9, 143–147 (1997).

    Article  CAS  Google Scholar 

  26. Watson, N., Linder, M.E., Druey, K.M., Kehrl, J.H. & Blumer, K.J. RGS family members: GTPase-activating proteins for heterotrimeric G-protein α-subunits. Nature 383, 172–175 (1996).

    Article  CAS  Google Scholar 

  27. Estes, J.D. et al. Follicular dendritic cell regulation of CXCR4-mediated germinal center CD4 T cell migration. J. Immunol. 173, 6169–6178 (2004).

    Article  CAS  Google Scholar 

  28. Moratz, C. et al. Regulator of G protein signaling 1 (RGS1) markedly impairs Gi α signaling responses of B lymphocytes. J. Immunol. 164, 1829–1838 (2000).

    Article  CAS  Google Scholar 

  29. Shi, G.X., Harrison, K., Wilson, G.L., Moratz, C. & Kehrl, J.H. RGS13 regulates germinal center B lymphocytes responsiveness to CXC chemokine ligand (CXCL)12 and CXCL13. J. Immunol. 169, 2507–2515 (2002).

    Article  CAS  Google Scholar 

  30. Armengol, M.P. et al. Chemokines determine local lymphoneogenesis and a reduction of circulating CXCR4+ T and CCR7 B and T lymphocytes in thyroid autoimmune diseases. J. Immunol. 170, 6320–6328 (2003).

    Article  CAS  Google Scholar 

  31. Lubberts, E. et al. IL-17 promotes bone erosion in murine collagen-induced arthritis through loss of the receptor activator of NF-κB ligand/osteoprotegerin balance. J. Immunol. 170, 2655–2662 (2003).

    Article  CAS  Google Scholar 

  32. Han, J.I., Huang, N.N., Kim, D.U. & Kehrl, J.H. RGS1 and RGS13 mRNA silencing in a human B lymphoma line enhances responsiveness to chemoattractants and impairs desensitization. J. Leukoc. Biol. 79, 1357–1368 (2006).

    Article  CAS  Google Scholar 

  33. Moratz, C., Hayman, J.R., Gu, H. & Kehrl, J.H. Abnormal B-cell responses to chemokines, disturbed plasma cell localization, and distorted immune tissue architecture in Rgs1−/− mice. Mol. Cell. Biol. 24, 5767–5775 (2004).

    Article  CAS  Google Scholar 

  34. Munthe, L.A., Corthay, A., Os, A., Zangani, M. & Bogen, B. Systemic autoimmune disease caused by autoreactive B cells that receive chronic help from Ig V region–specific T cells. J. Immunol. 175, 2391–2400 (2005).

    Article  CAS  Google Scholar 

  35. Marion, T.N., Krishnan, M.R., Steeves, M.A. & Desai, D.D. Affinity maturation and autoimmunity to DNA. Curr. Dir. Autoimmun. 6, 123–153 (2003).

    Article  Google Scholar 

  36. Fu, Y.X. & Storb, U. Immunology. Autoreactive B cells migrate into T cell territory. Science 297, 2006–2008 (2002).

    Article  CAS  Google Scholar 

  37. William, J., Euler, C., Christensen, S. & Shlomchik, M.J. Evolution of autoantibody responses via somatic hypermutation outside of germinal centers. Science 297, 2066–2070 (2002).

    Article  CAS  Google Scholar 

  38. Duan, B., Croker, B.P. & Morel, L. Lupus resistance is associated with marginal zone abnormalities in an NZM murine model. Lab. Invest. 87, 14–28 (2007).

    Article  CAS  Google Scholar 

  39. Bave, U. et al. FcγRIIa is expressed on natural IFN-α–producing cells (plasmacytoid dendritic cells) and is required for the IFN-α production induced by apoptotic cells combined with lupus IgG. J. Immunol. 171, 3296–3302 (2003).

    Article  CAS  Google Scholar 

  40. Meyers, J.A. et al. Blockade of TLR9 agonist-induced type I interferons promotes inflammatory cytokine IFN-γ and IL-17 secretion by activated human PBMC. Cytokine 35, 235–246 (2006).

    Article  CAS  Google Scholar 

  41. Williams, R.W. et al. Genetic structure of the LXS panel of recombinant inbred mouse strains: a powerful resource for complex trait analysis. Mamm. Genome 15, 637–647 (2004).

    Article  CAS  Google Scholar 

  42. Moratz, C., Harrison, K. & Kehrl, J.H. Regulation of chemokine-induced lymphocyte migration by RGS proteins. Methods Enzymol. 389, 15–32 (2004).

    Article  CAS  Google Scholar 

  43. Schwarzenberger, P. et al. IL-17 stimulates granulopoiesis in mice: use of an alternate, novel gene therapy-derived method for in vivo evaluation of cytokines. J. Immunol. 161, 6383–6389 (1998).

    CAS  PubMed  Google Scholar 

  44. Ye, P. et al. Requirement of interleukin 17 receptor signaling for lung CXC chemokine and granulocyte colony-stimulating factor expression, neutrophil recruitment, and host defense. J. Exp. Med. 194, 519–527 (2001).

    Article  CAS  Google Scholar 

  45. Muramatsu, M. et al. Class switch recombination and hypermutation require activation-induced cytidine deaminase (AID), a potential RNA editing enzyme. Cell 102, 553–563 (2000).

    Article  CAS  Google Scholar 

  46. Smith, K.G., Weiss, U., Rajewsky, K., Nossal, G.J. & Tarlinton, D.M. Bcl-2 increases memory B cell recruitment but does not perturb selection in germinal centers. Immunity 1, 803–813 (1994).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank Amgen for providing Il17r−/− B6 mice; E. Keyser and M.L. Spell (UAB FACS Core Facility) for operating the flow cytometry instrument; S. Williams (UAB High Resolution Imaging Facility) for acquiring confocal microscopic images; L. Harrington and C. Weaver for reagents and technical support in the TH-17 polarization experiments; F. Hunter for review of the manuscript; and C. Humber for secretarial assistance. This work was supported by the Arthritis Foundation (H.-C.H.), the American College of Rheumatology program (J.D.M. and R.H.C.), VA Merit Review Grants (J.D.M and R.H.C.), Daiichi-Sankyo (J.D.M.), and the National Institutes of Health (R24 DK64400 to R.G.L.).

Author information

Authors and Affiliations

  1. Departments of Medicine, University of Alabama at Birmingham, Birmingham, 35294, Alabama, USA

    Hui-Chen Hsu, PingAr Yang, John Wang, Qi Wu, Riley Myers, Jian Chen, Tanja Guentert, Robert H Carter & John D Mountz

  2. Microbiology, University of Alabama at Birmingham, Birmingham, 35294, Alabama, USA

    John Yi, Thuc-vy L Le & David D Chaplin

  3. Cell Biology, University of Alabama at Birmingham, Birmingham, 35294, Alabama, USA

    Albert Tousson

  4. Pathology, University of Alabama at Birmingham, Birmingham, 35294, Alabama, USA

    Andrea L Stanus & Robin G Lorenz

  5. Dermatology, University of Alabama at Birmingham, Birmingham, 35294, Alabama, USA

    Hui Xu

  6. Pediatric Pulmonology, Children's Hospital of Pittsburgh, Pittsburgh, 15213, Pennsylvania, USA

    Jay K Kolls

  7. Birmingham VA Medical Center, Birmingham, 35233, Alabama, USA

    Robert H Carter & John D Mountz

  8. Department of Anatomy and Neurobiology, University of Tennessee at Memphis, Memphis, 38152, Tennessee, USA

    Robert W Williams

Authors
  1. Hui-Chen Hsu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. PingAr Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. John Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Qi Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Riley Myers
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jian Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. John Yi
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Tanja Guentert
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Albert Tousson
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Andrea L Stanus
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Thuc-vy L Le
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Robin G Lorenz
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Hui Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Jay K Kolls
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Robert H Carter
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. David D Chaplin
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Robert W Williams
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. John D Mountz
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

H.-C.H. and J.D.M. contributed to all studies; P.A.Y. was involved in all animal experiments, FACS staining, chemotactic experiments, and all qPCR and RT-PCR experiments; J.W., R.M., A.T., A.L.S., R.G.L. and R.H.C. contributed to all immunohistochemistry staining, imaging acquiring and imaging data interpretation; Q.W. contributed to animal experiments, FACS staining, chemotactic experiments, and ELISA and ELISPOT analyses; J.C. contributed to FACS analysis and adenovirus propagation; J.Y. contributed to T cell polarization experiments and chemotactic experiments; J.K.K. contributed to the generation of AdIL-17 and AdIL-17R:Fc; T.G., H.X. and R.W.W. contributed to the generation of Il17r−/− BXD2 and GFP+ BXD2 mice; T.-v.L.L. and D.D.C. contributed to the studies of SHM analysis.

Corresponding authors

Correspondence to Hui-Chen Hsu or John D Mountz.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–5, Tables 1–3 and Methods (PDF 322 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Hsu, HC., Yang, P., Wang, J. et al. Interleukin 17–producing T helper cells and interleukin 17 orchestrate autoreactive germinal center development in autoimmune BXD2 mice. Nat Immunol 9, 166–175 (2008). https://doi.org/10.1038/ni1552

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ni1552

This article is cited by

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