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Sustained exposure to bacterial antigen induces interferon-γ-dependent T cell receptor ζ down-regulation and impaired T cell function

Nature Immunology volume 4, pages 957–964 (2003)Cite this article

Abstract

T cell antigen receptor ζ chain down-regulation and impaired in vitro T cell function have been described in cancer and autoimmune and infectious diseases. However, the immunological basis for this phenomenon is unknown. Sustained exposure to antigen and chronic systemic inflammation, factors shared by the various pathologies, might account for this phenomenon. We developed an in vivo experimental system that mimics these conditions and show that sustained exposure of mice to bacterial antigens was sufficient to induce T cell antigen receptor ζ chain down-regulation and impair T cell function, provided an interferon-γ-dependent T helper type 1 immune response developed. This indicates ζ chain down-regulation could be a physiological response that attenuates an exacerbated immune response. However, it can act as a 'double-edged sword', impairing immune responses to chronic diseases.

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Figure 1: Treatment with P. gingivalis induces specific ζ chain down-regulation.
Figure 2: Down-regulation of ζ is caused by enhanced lysosomal degradation.
Figure 3: T cells isolated from P. gingivalis– treated mice show impaired immune function.
Figure 4: Impaired ability of P. gingivalis–treated mice to clear an influenza infection.
Figure 5: Sustained exposure to antigen is necessary to induce ζ down-regulation.
Figure 6: A TH1 immune response is necessary for the induction of ζ chain down-regulation and T cell dysfunction.
Figure 7: IFN-γ mediates the induction of ζ chain down-regulation.

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References

  1. Weiss, A. & Littman, D.R. Signal transduction by lymphocyte antigen receptors. Cell 76, 263–274 (1994).

    Article  CAS  Google Scholar 

  2. Klausner, R.D., Lippincott-Schwartz, J. & Bonifacino, J.S. The T cell antigen receptor: insights into organelle biology. Annu. Rev. Cell Biol. 6, 403–431 (1990).

    Article  CAS  Google Scholar 

  3. Mizoguchi, H. et al. Alterations in signal transduction molecules in T lymphocytes from tumor-bearing mice. Science 258, 1795–178 (1992).

    Article  CAS  Google Scholar 

  4. Kane, L.P., Lin, J. & Weiss, A. Signal transduction by the TCR for antigen. Curr. Opin. Immunol. 12, 242–249 (2000).

    Article  CAS  Google Scholar 

  5. Alberola-Ila, J., Takaki, S., Kerner, J.D. & Perlmutter, R.M. Differential signaling by lymphocyte antigen receptors. Annu. Rev. Immunol. 15, 125–154 (1997).

    Article  CAS  Google Scholar 

  6. Finke, J.H. et al. Loss of T-cell receptor ζ chain and p56lck in T-cells infiltrating human renal cell carcinoma. Cancer Res. 53, 5613–5616 (1993).

    CAS  PubMed  Google Scholar 

  7. Nakagomi, H. et al. Decreased expression of the signal-transducing ζ chains in tumor-infiltrating T-cells and NK cells of patients with colorectal carcinoma. Cancer Res. 53, 5610–5612 (1993).

    CAS  PubMed  Google Scholar 

  8. Matsuda, M. et al. Alterations in the signal-transducing molecules of T cells and NK cells in colorectal tumor-infiltrating, gut mucosal and peripheral lymphocytes: correlation with the stage of the disease. Int. J. Cancer 61, 765–772 (1995).

    Article  CAS  Google Scholar 

  9. Lai, P. et al. Alterations in expression and function of signal-transducing proteins in tumor-associated T and natural killer cells in patients with ovarian carcinoma. Clin. Cancer Res. 2, 161–173 (1996).

    CAS  PubMed  Google Scholar 

  10. Kono, K. et al. Decreased expression of signal-transducing ζ chain in peripheral T cells and natural killer cells in patients with cervical cancer. Clin. Cancer Res. 2, 1825–1828 (1996).

    CAS  PubMed  Google Scholar 

  11. Kurt, R.A., Urba, W.J., Smith, J.W. & Schoof, D.D. Peripheral T lymphocytes from women with breast cancer exhibit abnormal protein expression of several signaling molecules. Int. J. Cancer 78, 16–20 (1998).

    Article  CAS  Google Scholar 

  12. Kuss, I., Saito, T., Johnson, J.T. & Whiteside, T.L. Clinical significance of decreased ζ chain expression in peripheral blood lymphocytes of patients with head and neck cancer. Clin. Cancer Res. 5, 329–334 (1999).

    CAS  PubMed  Google Scholar 

  13. Healy, C.G. et al. Impaired expression and function of signal-transducing ζ chains in peripheral T cells and natural killer cells in patients with prostate cancer. Cytometry 32, 109–119 (1998).

    Article  CAS  Google Scholar 

  14. Trimble, L.A. & Lieberman, J. Circulating CD8 T lymphocytes in human immunodeficiency virus-infected individuals have impaired function and downmodulate CD3 ζ, the signaling chain of the T-cell receptor complex. Blood 91, 585–594 (1998).

    CAS  PubMed  Google Scholar 

  15. Zea, A.H. et al. Changes in expression of signal transduction proteins in T lymphocytes of patients with leprosy. Infect. Immun. 66, 499–504 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Maurice, M.M. et al. Defective TCR-mediated signaling in synovial T cells in rheumatoid arthritis. J. Immunol. 159, 2973–2978 (1997).

    CAS  PubMed  Google Scholar 

  17. Liossis, S.N., Ding, X.Z., Dennis, G.J. & Tsokos, G.C. Altered pattern of TCR/CD3-mediated protein-tyrosyl phosphorylation in T cells from patients with systemic lupus erythematosus. Deficient expression of the T cell receptor ζ chain. J. Clin. Invest. 101, 1448–1457 (1998).

    Article  CAS  Google Scholar 

  18. Genco, C.A. & Arko, R.J. Animal chamber models for study of host-parasite interactions. Methods Enzymol. 235, 120–140 (1994).

    Article  CAS  Google Scholar 

  19. Houri-Haddad, Y., Soskolne, W.A., Halabi, A., Barak, V. & Shapira, L. Repeat bacterial challenge in a subcutaneous chamber model results in augmented tumour necrosis factor-α and interferon-γ response, and suppression of interleukin-10. Immunology 99, 215–220 (2000).

    Article  CAS  Google Scholar 

  20. Franco, J.L. et al. Partial degradation of T-cell signal transduction molecules by contaminating granulocytes during protein extraction of splenic T cells from tumor-bearing mice. Cancer Res. 55, 3840–3846 (1995).

    CAS  PubMed  Google Scholar 

  21. Caplan, S. & Baniyash, M. Normal T cells express two T cell antigen receptor populations, one of which is linked to the cytoskeleton via ζ chain and displays a unique activation-dependent phosphorylation pattern. J. Biol. Chem. 271, 20705–20712 (1996).

    Article  CAS  Google Scholar 

  22. Caplan, S., Zeliger, S., Wang, L. & Baniyash, M. Cell-surface-expressed T-cell antigen-receptor ζ chain is associated with the cytoskeleton. Proc. Natl. Acad. Sci. USA 92, 4768–4772 (1995).

    Article  CAS  Google Scholar 

  23. Bronstein-Sitton, N., Wang, L., Cohen, L. & Baniyash, M. Expression of the T cell antigen receptor ζ chain following activation is controlled at distinct checkpoints. Implications for cell surface receptor down-modulation and re-expression. J. Biol. Chem. 274, 23659–23665 (1999).

    Article  CAS  Google Scholar 

  24. Valitutti, S., Muller, S., Salio, M. & Lanzavecchia, A. Degradation of T cell receptor (TCR)-CD3-ζ complexes after antigenic stimulation. J. Exp. Med. 185, 1859–1864 (1997).

    Article  CAS  Google Scholar 

  25. D'Oro, U., Vacchio, M.S., Weissman, A.M. & Ashwell, J.D. Activation of the Lck tyrosine kinase targets cell surface T cell antigen receptors for lysosomal degradation. Immunity 7, 619–628 (1997).

    Article  CAS  Google Scholar 

  26. Wells, M.A., Ennis, F.A. & Albrecht, P. Recovery from a viral respiratory infection. II. Passive transfer of immune spleen cells to mice with influenza pneumonia. J. Immunol. 126, 1042–1046 (1981).

    CAS  PubMed  Google Scholar 

  27. Ada, G.L. & Jones, P.D. The immune response to influenza infection. Curr. Top. Microbiol. Immunol. 128, 1–54 (1986).

    Article  CAS  Google Scholar 

  28. Gerhard, W., Mozdzanowska, K., Furchner, M., Washko, G. & Maiese, K. Role of the B-cell response in recovery of mice from primary influenza virus infection. Immunol. Rev. 159, 95–103 (1997).

    Article  CAS  Google Scholar 

  29. Spellberg, B. & Edwards, J.E., Jr. Type 1/Type 2 immunity in infectious diseases. Clin. Infect. Dis. 32, 76–102 (2001).

    Article  CAS  Google Scholar 

  30. Correa, M.R. et al. Sequential development of structural and functional alterations in T cells from tumor-bearing mice. J. Immunol. 158, 5292–5296 (1997).

    CAS  Google Scholar 

  31. Sussman, J.J. et al. Failure to synthesize the T cell CD3-ζ chain: structure and function of a partial T cell receptor complex. Cell 52, 85–95 (1988).

    Article  CAS  Google Scholar 

  32. Enyedy, E.J. et al. Fcε receptor type I γ chain replaces the deficient T cell receptor ζ chain in T cells of patients with systemic lupus erythematosus. Arthritis Rheum. 44, 1114–1121 (2001).

    Article  CAS  Google Scholar 

  33. Houri-Haddad, Y., Soskolne, W.A., Shai, E., Palmon, A. & Shapira, L. Interferon-γ deficiency attenuates local P. gingivalis-induced inflammation. J. Dent. Res. 81, 395–398 (2002).

    Article  CAS  Google Scholar 

  34. Frucht, D.M. et al. IFN-γ production by antigen-presenting cells: mechanisms emerge. Trends Immunol. 22, 556–560 (2001).

    Article  CAS  Google Scholar 

  35. Otsuji, M., Kimura, Y., Aoe, T., Okamoto, Y. & Saito, T. Oxidative stress by tumor-derived macrophages suppresses the expression of CD3 ζ chain of T-cell receptor complex and antigen-specific T-cell responses. Proc. Natl. Acad. Sci. USA 93, 13119–13124 (1996).

    Article  CAS  Google Scholar 

  36. Almand, B. et al. Increased production of immature myeloid cells in cancer patients: a mechanism of immunosuppression in cancer. J. Immunol. 166, 678–689 (2001).

    Article  CAS  Google Scholar 

  37. Kono, K. et al. Hydrogen peroxide secreted by tumor-derived macrophages down-modulates signal-transducing ζ molecules and inhibits tumor-specific T cell and natural killer cell-mediated cytotoxicity. Eur. J. Immunol. 26, 1308–1313 (1996).

    Article  CAS  Google Scholar 

  38. Schmielau, J. & Finn, O.J. Activated granulocytes and granulocyte-derived hydrogen peroxide are the underlying mechanism of suppression of T-cell function in advanced cancer patients. Cancer Res. 61, 4756–4760 (2001).

    CAS  PubMed  Google Scholar 

  39. Kusmartsev, S.A., Li, Y. & Chen, S.H. Gr-1+ myeloid cells derived from tumor-bearing mice inhibit primary T cell activation induced through CD3/CD28 costimulation. J. Immunol. 165, 779–785 (2000).

    Article  CAS  Google Scholar 

  40. Baker, P.J., Evans, R.T. & Roopenian, D.C. Oral infection with Porphyromonas gingivalis and induced alveolar bone loss in immunocompetent and severe combined immunodeficient mice. Arch. Oral Biol. 39, 1035–1040 (1994).

    Article  CAS  Google Scholar 

  41. Kesavalu, L., Ebersole, J.L., Machen, R.L. & Holt, S.C. Porphyromonas gingivalis virulence in mice: induction of immunity to bacterial components. Infect. Immun. 60, 1455–1464 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Rozdzial, M.M., Kubo, R.T., Turner, S.L. & Finkel, T.H. Developmental regulation of the TCR ζ-chain. Differential expression and tyrosine phosphorylation of the TCR ζ-chain in resting immature and mature T lymphocytes. J. Immunol. 153, 1563–1580 (1994).

    CAS  PubMed  Google Scholar 

  43. Samelson, L.E., Weissman, A.M., Robey, F.A., Berkower, I. & Klausner, R.D. Characterization of an anti-peptide antibody that recognizes the murine analogue of the human T cell antigen receptor-T3 δ-chain. J. Immunol. 137, 3254–3258 (1986).

    CAS  PubMed  Google Scholar 

  44. Harlow, E. & Lane, D. Using Antibodies: A Laboratory Manual (eds. Harlow, E. & Lane, D.) (Cold Spring Harbor Laboratory Press, Cold Spring Harbor, New York, 1999).

    Google Scholar 

  45. Leshem, B., Yogev, D. & Fiorentini, D. Heat inactivation of fetal calf serum is not required for in vitro measurement of lymphocyte functions. J. Immunol. Meth. 223, 249–254 (1999).

    Article  CAS  Google Scholar 

  46. Leshem, B. & Brass, D. Mouse lymphoblasts lose their immunogenicity and susceptibility to specific cytotoxic T lymphocyte lysis during maintenance in culture. Immunology 95, 409–418 (1998).

    Article  CAS  Google Scholar 

  47. Abdul-Hai, A. et al. Interleukin-7-enhanced cytotoxic T lymphocyte activity after viral infection in marrow transplanted mice. Bone Marrow Transplant. 19, 539–543 (1997).

    Article  CAS  Google Scholar 

  48. Reed, J.L. & Muench, M. A simple method of estimating fifty percent endpoint. Am. J. Hyg. 27, 493–497 (1938).

    Google Scholar 

  49. Frolov, I., Houri-Hadad, Y., Soskolne, A. & Shapira, L. In vivo exposure to Porphyromonas gingivalis up-regulates nitric oxide but suppresses tumour necrosis factor-α production by cultured macrophages. Immunology 93, 323–328 (1998).

    Article  CAS  Google Scholar 

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Acknowledgements

We thank N. Rosenheimer-Goudsmid for help with the FACS analysis. Supported by the Society of Research Associates of the Lautenberg Center, the Concern Foundation of Los Angeles, the Israel Academy of Sciences and Humanities, and the Joseph and Matilda Melnick Fund.

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Author notes

  1. Noemí Bronstein-Sitton and Leonor Cohen-Daniel: These authors contributed equally to this work.

Authors and Affiliations

  1. The Lautenberg Center for General and Tumor Immunology, The Hebrew University-Hadassah Medical School, Jerusalem, 91120, Israel

    Noemí Bronstein-Sitton, Leonor Cohen-Daniel, Ilan Vaknin, Analía V Ezernitchi, Benny Leshem & Michal Baniyash

  2. Department of Periodontology, The Hebrew University-Hadassah Faculty of Dental Medicine, Jerusalem, 91120, Israel

    Amal Halabi, Yael Houri-Hadad & Lior Shapira

  3. Department of Virology, The Hebrew University-Hadassah Medical School, Jerusalem, 91120, Israel

    Eugenia Greenbaum & Zichria Zakay-Rones

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Bronstein-Sitton, N., Cohen-Daniel, L., Vaknin, I. et al. Sustained exposure to bacterial antigen induces interferon-γ-dependent T cell receptor ζ down-regulation and impaired T cell function. Nat Immunol 4, 957–964 (2003). https://doi.org/10.1038/ni975

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