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  • Opinion
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Regulation of T-helper-cell lineage development by osteopontin: the inside story

Abstract

Studies of osteopontin (OPN)-dependent regulation of immune responses have focused on the cytokine activities of the secreted form of this protein. Recent evidence has revealed that an intracellular form of OPN expressed by dendritic cells regulates the expression of pro-inflammatory cytokines and the differentiation of T helper (TH)-cell lineages. In this Opinion article, we discuss the properties of both OPN isoforms and their respective contributions to the immune response. We propose that cell-type-specific expression of secreted and intracellular OPN regulates the development of distinct effector TH cells, including that of TH1 and TH17 cells.

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Figure 1: Alternative translational mechanism that generates sOPN and iOPN.
Figure 2: T-helper-cell polarization by osteopontin isoforms expressed by different cell types.
Figure 3: Osteopontin-mediated regulation of pathogenic CD4+ T cells in experimental autoimmune encephalomyelitis.

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References

  1. Ashkar, S. et al. Eta-1 (osteopontin): an early component of type 1 (cell-mediated) immunity. Science 287, 860–864 (2000).

    Article  CAS  PubMed  Google Scholar 

  2. Shinohara, M. L. et al. T-bet-dependent expression of osteopontin contributes to T cell polarization. Proc. Natl Acad. Sci USA 102, 17101–17106 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Weiss, J. M. et al. Osteopontin is involved in the initiation of cutaneous contact hypersensitivity by inducing Langerhans and dendritic cell migration to lymph nodes. J. Exp. Med. 194, 1219–1229 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Zohar, R. et al. Single cell analysis of intracellular osteopontin in osteogenic cultures of fetal rat calvarial cells. J. Cell Physiol. 170, 88–100 (1997).

    Article  CAS  PubMed  Google Scholar 

  5. Zohar, R. et al. Intracellular osteopontin is an integral component of the CD44–ERM complex involved in cell migration. J. Cell Physiol. 184, 118–130 (2000).

    Article  CAS  PubMed  Google Scholar 

  6. Suzuki, K. et al. Colocalization of intracellular osteopontin with CD44 is associated with migration, cell fusion, and resorption in osteoclasts. J. Bone Miner. Res. 17, 1486–1497 (2002).

    Article  CAS  PubMed  Google Scholar 

  7. Zhu, B. et al. Osteopontin modulates CD44-dependent chemotaxis of peritoneal macrophages through G-protein-coupled receptors: evidence of a role for an intracellular form of osteopontin. J. Cell Physiol. 198, 155–167 (2004).

    Article  CAS  PubMed  Google Scholar 

  8. Shinohara, M. L., Kim, H.-J., Kim, J.-H., Garcia, V. A. & Cantor, H. Alternative translation of osteopontin generates intracellular and secreted isoforms that mediate distinct biological activities in dendritic cells. Proc. Natl Acad. Sci. USA 105, 7235–7239 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Shinohara, M. L. et al. Osteopontin expression is essential for IFN-α production by plasmacytoid dendritic cells. Nature Immunol. 7, 498–506 (2006).

    Article  CAS  Google Scholar 

  10. Maeno, Y. et al. Osteopontin participates in Th1-mediated host resistance against nonlethal malaria parasite Plasmodium chabaudi chabaudi infection in mice. Infect. Immun. 74, 2423–2427 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Shinohara, M. L., Kim, J.-H., Garcia, V. A. & Cantor, H. Engagement of the type-I interferon receptor on dendritic cells inhibits promotion of Th17 cells: role of intracellular osteopontin. Immunity 29, 68–78 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Patarca, R. et al. Structural and functional studies of the early T lymphocyte activation 1 (Eta-1) gene. Definition of a novel T cell-dependent response associated with genetic resistance to bacterial infection. J. Exp. Med. 170, 145–161 (1989).

    Article  CAS  PubMed  Google Scholar 

  13. Fet, V., Dickinson, M. E. & Hogan, B. L. Localization of the mouse gene for secreted phosphoprotein 1 (Spp1) (2ar, osteopontin, bone sialoprotein 1, 44kDa bone phosphoprotein, tumor-secreted phosphoprotein) to chromosome 5, closely linked to Ric (Rickettsia resistance). Genomics 5, 375–377 (1989).

    Article  CAS  PubMed  Google Scholar 

  14. Weber, G. F., Ashkar, S., Glimcher, M. J. & Cantor, H. Receptor–ligand interaction between CD44 and osteopontin/Eta-1. Science 271, 509–512 (1996).

    Article  CAS  PubMed  Google Scholar 

  15. Nau, G. J. et al. Attenuated host resistance against Mycobacterium bovis BCG infection in mice lacking osteopontin. Infect. Immun. 67, 4223–4230 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Nau, G. J. et al. Osteopontin expression correlates with clinical outcome in patients with mycobacterial infection. Am. J. Pathol. 157, 37–42 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Koguchi, Y. et al. High plasma osteopontin level and its relationship with interleukin-12-mediated type 1 helper cell response in tuberculosis. Am. J. Respir. Crit. Care Med. 167, 1355–1359 (2003).

    Article  PubMed  Google Scholar 

  18. Kadota, J. et al. High plasma concentrations of osteopontin in patients with interstitial pneumonia. Respir. Med. 99, 111–117 (2005).

    Article  CAS  PubMed  Google Scholar 

  19. Rollo, E. E. et al. The cytokine osteopontin modulates the severity of rotavirus diarrhea. J. Virol. 79, 3509–3516 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Erb, K. J., Kirman, J., Delahunt, B., Chen, W. & Le Gros, G. IL-4, IL-5 and IL-10 are not required for the control of M. bovis-BCG infection in mice. Immunol. Cell Biol. 76, 41–46 (1998).

    Article  CAS  PubMed  Google Scholar 

  21. Abel, B., Freigang, S., Bachmann, M. F., Boschert, U. & Kopf, M. Osteopontin is not required for the development of Th1 responses and viral immunity. J. Immunol. 175, 6006–6013 (2005).

    Article  CAS  PubMed  Google Scholar 

  22. Craig-Mylius, K., Weber, G. F., Coburn, J. & Glickstein, L. Borrelia burgdorferi, an extracellular pathogen, circumvents osteopontin in inducing an inflammatory cytokine response. J. Leukoc. Biol. 77, 710–718 (2005).

    Article  CAS  PubMed  Google Scholar 

  23. Barchet, W. et al. Dendritic cells respond to influenza virus through TLR7- and PKR-independent pathways. Eur. J. Immunol. 35, 236–242 (2005).

    Article  CAS  PubMed  Google Scholar 

  24. Lazarus, J. J., Meadows, M. J., Lintner, R. E. & Wooten, R. M. IL-10 deficiency promotes increased Borrelia burgdorferi clearance predominantly through enhanced innate immune responses. J. Immunol. 177, 7076–7085 (2006).

    Article  CAS  PubMed  Google Scholar 

  25. Patarca, R., Wei, F.-Y., Singh, P., Morasso, M. I. & Cantor, H. Dysregulated expression of the T-cell cytokine Eta-1 in CD4-8- lymphocytes during the development of murine autoimmune disease. J. Exp. Med. 172, 1177–1183 (1990).

    Article  CAS  PubMed  Google Scholar 

  26. Miyazaki, T. et al. Implication of allelic polymorphism of osteopontin in the development of lupus nephritis in MRL/lpr mice. Eur. J. Immunol. 35, 1510–1520 (2005).

    Article  CAS  PubMed  Google Scholar 

  27. Chiocchetti, A. et al. High levels of osteopontin associated with polymorphisms in its gene are a risk factor for development of autoimmunity/lymphoproliferation. Blood 103, 1376–1382 (2004).

    Article  CAS  PubMed  Google Scholar 

  28. Forton, A. C., Petri, M. A., Goldman, D. & Sullivan, K. E. An osteopontin (SPP1) polymorphism is associated with systemic lupus erythematosus. Hum. Mutat. 19, 459 (2002).

    Article  CAS  PubMed  Google Scholar 

  29. D'Alfonso, S. et al. Two single-nucleotide polymorphisms in the 5′ and 3′ ends of the osteopontin gene contribute to susceptibility to systemic lupus erythematosus. Arthritis Rheum. 52, 539–547 (2005).

    Article  CAS  PubMed  Google Scholar 

  30. Yumoto, K. et al. Osteopontin deficiency protects joints against destruction in anti-type II collagen antibody-induced arthritis in mice. Proc. Natl Acad. Sci. USA 99, 4556–4561 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Yamamoto, N. et al. Essential role of the cryptic epitope SLAYGLR within osteopontin in a murine model of rheumatoid arthritis. J. Clin. Invest. 112, 181–188 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Yamamoto, N. et al. Successful treatment of collagen-induced arthritis in non-human primates by chimeric anti-osteopontin antibody. Int. Immunopharmacol. 7, 1460–1470 (2007).

    Article  CAS  PubMed  Google Scholar 

  33. Ishii, T. et al. Mice with osteopontin deletion remain predisposed to collagen-induced arthritis. Arthritis Rheum. 50, 669–671 (2004).

    Article  CAS  PubMed  Google Scholar 

  34. Jacobs, J. P. et al. Lack of requirement of osteopontin for inflammation, bone erosion, and cartilage damage in the K/BxN model of autoantibody-mediated arthritis. Arthritis Rheum. 50, 2685–2694 (2004).

    Article  CAS  PubMed  Google Scholar 

  35. Xanthou, G. et al. A critical role for osteopontin in T helper type 2 allergic airway disease: regulation of plasmacytoid and conventional dendritic cell subsets. Nature Med. 13, 570–578 (2007).

    Article  CAS  PubMed  Google Scholar 

  36. Shinohara, M. L. & Cantor, H. The bridge between dendritic cells and asthma. Nature Med. 13, 536–538 (2007).

    Article  CAS  PubMed  Google Scholar 

  37. Junaid, A., Moon, M. C., Harding, G. E. & Zahradka, P. Osteopontin localizes to the nucleus of 293 cells and associates with polo-like kinase-1. Am. J. Physiol. Cell Physiol. 292, C919–C926 (2007).

    Article  CAS  PubMed  Google Scholar 

  38. Bellahcene, A., Castronovo, V., Ogbureke, K. U., Fisher, L. W. & Fedarko, N. S. Small integrin-binding ligand N-linked glycoproteins (SIBLINGs): multifunctional proteins in cancer. Nature Rev. Cancer 8, 212–226 (2008).

    Article  CAS  Google Scholar 

  39. Prinz, M. et al. Distinct and nonredundant in vivo functions of IFNAR on myeloid cells limit autoimmunity in the central nervous system. Immunity 28, 675–686 (2008).

    Article  CAS  PubMed  Google Scholar 

  40. Brinkmann, V., Geiger, T., Alkan, S. & Heusser, C. H. Interferon α increases the frequency of interferon γ-producing human CD4+ T cells. J. Exp. Med. 178, 1655–1663 (1993).

    Article  CAS  PubMed  Google Scholar 

  41. Cousens, L. P. et al. Two roads diverged: interferon α/β- and interleukin-12-mediated pathways in promoting T cell interferon γ responses during viral infection. J. Exp. Med. 189, 1315–1327 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Montoya, M. et al. Type I interferons produced by dendritic cells promote their phenotypic and functional activation. Blood 99, 3263–3271 (2002).

    Article  CAS  PubMed  Google Scholar 

  43. Burchill, M. A. et al. Inhibition of interleukin-17 prevents the development of arthritis in vaccinated mice challenged with Borrelia burgdorferi. Infect. Immun. 71, 3437–3442 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Leibundgut-Landmann, S. et al. Syk- and CARD9-dependent coupling of innate immunity to the induction of T helper cells that produce interleukin 17. Nature Immunol. 8, 630–638 (2007).

    Article  CAS  Google Scholar 

  45. Chabaud, M., Fossiez, F., Taupin, J. L. & Miossec, P. Enhancing effect of IL-17 on IL-1-induced IL-6 and leukemia inhibitory factor production by rheumatoid arthritis synoviocytes and its regulation by Th2 cytokines. J. Immunol. 161, 409–414 (1998).

    CAS  PubMed  Google Scholar 

  46. Kotake, S. et al. IL-17 in synovial fluids from patients with rheumatoid arthritis is a potent stimulator of osteoclastogenesis. J. Clin. Invest. 103, 1345–1352 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Matusevicius, D. et al. Interleukin-17 mRNA expression in blood and CSF mononuclear cells is augmented in multiple sclerosis. Mult. Scler. 5, 101–104 (1999).

    Article  CAS  PubMed  Google Scholar 

  48. Wong, C. K., Ho, C. Y., Li, E. K. & Lam, C. W. Elevation of proinflammatory cytokine (IL-18, IL-17, IL-12) and Th2 cytokine (IL-4) concentrations in patients with systemic lupus erythematosus. Lupus 9, 589–593 (2000).

    Article  CAS  PubMed  Google Scholar 

  49. Lock, C. et al. Gene-microarray analysis of multiple sclerosis lesions yields new targets validated in autoimmune encephalomyelitis. Nature Med. 8, 500–508 (2002).

    Article  CAS  PubMed  Google Scholar 

  50. Duerr, R. H. et al. A genome-wide association study identifies IL23R as an inflammatory bowel disease gene. Science 314, 1461–1463 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Batten, M. et al. Interleukin 27 limits autoimmune encephalomyelitis by suppressing the development of interleukin 17-producing T cells. Nature Immunol. 7, 929–936 (2006).

    Article  CAS  Google Scholar 

  52. Stumhofer, J. S. et al. Interleukin 27 negatively regulates the development of interleukin 17-producing T helper cells during chronic inflammation of the central nervous system. Nature Immunol. 7, 937–945 (2006).

    Article  CAS  Google Scholar 

  53. Guo, B., Chang, E. Y. & Cheng, G. The type I IFN induction pathway constrains Th17-mediated autoimmune inflammation in mice. J. Clin. Invest. 118, 1680–1690 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Chabas, D. et al. The influence of the proinflammatory cytokine, osteopontin, on autoimmune demyelinating disease. Science 294, 1731–1735 (2001).

    Article  CAS  PubMed  Google Scholar 

  55. Jansson, M., Panoutsakopoulou, V., Baker, J., Klein, L. & Cantor, H. Attenuated experimental autoimmune encephalomyelitis in Eta-1/osteopontin-deficient mice. J. Immunol. 168, 2096–2099 (2002).

    Article  CAS  PubMed  Google Scholar 

  56. Blom, T., Franzen, A., Heinegard, D. & Holmdahl, R. Comment on “The influence of the proinflammatory cytokine, osteopontin, on autoimmune demyelinating disease”. Science 299, 1845 (2003).

    Article  CAS  PubMed  Google Scholar 

  57. Hur, E. M. et al. Osteopontin-induced relapse and progression of autoimmune brain disease through enhanced survival of activated T cells. Nature Immunol. 8, 74–83 (2007).

    Article  CAS  Google Scholar 

  58. Paty, D. W. & Li, D. K. Interferon β-1b is effective in relapsing-remitting multiple sclerosis. II. MRI analysis results of a multicenter, randomized, double-blind, placebo-controlled trial. UBC MS/MRI Study Group and the IFNB Multiple Sclerosis Study Group. Neurology 43, 662–667 (1993).

    Article  CAS  PubMed  Google Scholar 

  59. Langer, J. A. Interferon at 50: new molecules, new potential, new (and old) questions. Sci. STKE 2007, e53 (2007).

    Article  Google Scholar 

  60. Brideau-Andersen, A. D. et al. Directed evolution of gene-shuffled IFN-α molecules with activity profiles tailored for treatment of chronic viral diseases. Proc. Natl Acad. Sci. USA 104, 8269–8274 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Axtell, R. C. & Steinman, L. Type 1 interferons cool the inflamed brain. Immunity 28, 600–602 (2008).

    Article  CAS  PubMed  Google Scholar 

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Correspondence to Harvey Cantor.

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Cantor, H., Shinohara, M. Regulation of T-helper-cell lineage development by osteopontin: the inside story. Nat Rev Immunol 9, 137–141 (2009). https://doi.org/10.1038/nri2460

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