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:

Interaction of Tim-3 and Tim-3 ligand regulates T helper type 1 responses and induction of peripheral tolerance

Nature Immunology volume 4, pages 1102–1110 (2003)Cite this article

Abstract

T helper type 1 (TH1) immune responses are central in cell-mediated immunity, and a TH1-specific cell surface molecule called Tim-3 (T cell immunoglobulin domain, mucin domain) has been identified. Here we report the identification of a secreted form of Tim-3 that contains only the immunoglobulin (Ig) variable (V) domain of the full-length molecule. Fusion proteins (Tim-3–Ig) of both Tim-3 isoforms specifically bound CD4+ T cells, indicating that a Tim-3 ligand is expressed on CD4+ T cells. Administration of Tim-3–Ig to immunized mice caused hyperproliferation of TH1 cells and TH1 cytokine release. Tim-3–Ig also abrogated tolerance induction in TH1 cells, and Tim-3-deficient mice were refractory to the induction of high-dose tolerance. These data indicate that interaction of Tim-3 with Tim-3 ligand may serve to inhibit effector TH1 cells during a normal immune response and may be crucial for the induction of peripheral tolerance.

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: Identification of alternatively spliced soluble form of Tim-3.
Figure 2: Tim-3L is expressed on CD4+ T cells.
Figure 3: Administration of Tim-3–Ig induces hyperproliferation and spontaneous production of TH1 cytokines.
Figure 4: Spontaneous hyperproliferation and cytokine release is mediated by T cells.
Figure 5: Administration of Tim-3–Ig prevents tolerance induction.
Figure 6: Tim-3-deficient mice are refractory to high-dose tolerance induction.

Similar content being viewed by others

References

  1. Mosmann, T., Cherwinski, H., Bond, M., Giedlin, M. & Coffman, R. Two types of murine helper T cell clone. I. Definition according to profiles of lymphokine activities and secreted proteins. J. Immunol. 136, 2348–2357 (1986).

    CAS  PubMed  Google Scholar 

  2. Mosmann, T. & Sad, S. The expanding universe of T-cell subsets: TH1, TH2 and more. Immunol. Today 19, 138–146 (1996).

    Article  Google Scholar 

  3. Abbas, A., Murphy, K. & Sher, A. Functional diversity of helper T lymphocytes. Nature 383, 787–793 (1996).

    Article  CAS  Google Scholar 

  4. Sher, A. & Coffman, R. Regulation of immunity to parasites by T cells and T cell-derived cytokines. Annu. Rev. Immunol. 10, 385–409 (1992).

    Article  CAS  Google Scholar 

  5. Liblau, R., Singer, S. & McDevitt, H. TH1 and TH2 CD4+ T cells in the pathogenesis of organ-specific autoimmune diseases. Immunol. Today 16, 34–38 (1995).

    Article  CAS  Google Scholar 

  6. Nicholson, L., Greer, J., Sobel, R., Lees, M. & Kuchroo, V. An altered peptide ligand mediates immune deviation and prevents autoimmune encephalomyelitis. Immunity 3, 397–405 (1995).

    Article  CAS  Google Scholar 

  7. Kuchroo, V. et al. B7-1 and B7-2 costimulatory molecules activate differentially the TH1/TH2 developmental pathways: application to autoimmune disease therapy. Cell 80, 707–718 (1995).

    Article  CAS  Google Scholar 

  8. Lack, G. et al. Nebulized but not parenteral IFN-γ decreases IgE production and normalizes airways function in a murine model of allergen sensitization. J. Immunol. 152, 2546–2554 (1994).

    CAS  PubMed  Google Scholar 

  9. Hofstra, C. et al. Prevention of TH2-like cell responses by coadministration of IL-12 and IL-18 is associated with inhibition of antigen-induced airway hyperresponsiveness, eosinophilia, and serum IgE levels. J. Immunol. 161, 5054–5060 (1998).

    CAS  PubMed  Google Scholar 

  10. Syrbe, U., Siveke, J. & Hamann, A. TH1/TH2 subsets: distinct differences in homing and chemokine receptor expression? Springer Semin. Immunopathol. 21, 263–285 (1999).

    Article  CAS  Google Scholar 

  11. Loetscher, P. et al. CCR5 is characteristic of TH1 lymphocytes. Nature 391, 344–345 (1998).

    Article  CAS  Google Scholar 

  12. Bonecchi, R. et al. Differential expression of chemokine receptors and chemotactic responsiveness of type 1 T helper cells (TH1s) and TH2s. J. Exp. Med. 187, 129–134 (1998).

    Article  CAS  Google Scholar 

  13. Sallusto, F., Lenig, D., Mackay, C. & Lanzavecchia, A. Flexible programs of chemokine receptor expression on human polarized T helper 1 and 2 lymphocytes. J. Exp. Med. 187, 875–883 (1998).

    Article  CAS  Google Scholar 

  14. Venkataraman, C., Schaefer, G. & Schindler, U. Cutting edge: Chandra, a novel four-transmembrane domain protein differentially expressed in helper type 1 lymphocytes. J. Immunol. 165, 632–636 (2000).

    Article  CAS  Google Scholar 

  15. Jourdan, P. et al. IL-4 induces functional cell-surface expression of CXCR4 on human T cells. J. Immunol. 160, 4153–4157 (1998).

    CAS  PubMed  Google Scholar 

  16. Lohning, M. et al. T1/ST2 is preferentially expressed on murine TH2 cells, independent of interleukin 4, interleukin 5, and interleukin 10, and important for TH2 effector function. Proc. Natl. Acad. Sci. USA 95, 6930–6935 (1998).

    Article  CAS  Google Scholar 

  17. McAdam, A. et al. Mouse inducible costimulatory molecule (ICOS) expression is enhanced by CD28 costimulation and regulates differentiation of CD4+ T cells. J. Immunol. 165, 5035–5040 (2000).

    Article  CAS  Google Scholar 

  18. Zingoni, A. et al. The chemokine receptor CCR8 is preferentially expressed in TH2 but not TH1 cells. J. Immunol. 161, 547–551 (1998).

    CAS  PubMed  Google Scholar 

  19. McIntire, J. et al. Identification of Tapr (an airway hyperreactivity regulatory locus) and the linked Tim gene family. Nat. Immunol. 2, 1109–1116 (2001).

    Article  CAS  Google Scholar 

  20. Monney, L. et al. TH1-specific cell surface protein Tim-3 regulates macrophage activation and severity of an autoimmune disease. Nature 415, 536–541 (2002).

    Article  CAS  Google Scholar 

  21. Zheng, X. et al. Administration of noncytolytic IL-10/Fc in murine models of lipopolysaccharide-induced septic shock and allogeneic islet transplantation. J Immunol 154, 5590–5600 (1995).

    CAS  PubMed  Google Scholar 

  22. Sanchez-Fueyo, A. et al. Tim-3 inhibits T helper type 1–mediated auto- and alloimmune responses and promotes immunological tolerance. Nat. Immunol. advanced online publication 12 October 2003; doi:10.1038/ni987.

  23. Perez, V. et al. Induction of peripheral T cell tolerance in vivo requires CTLA-4 engagement. Immunity 6, 411–417 (1997).

    Article  CAS  Google Scholar 

  24. Burstein, H. & Abbas, A. In vivo role of interleukin 4 in T cell tolerance induced by aqueous protein antigen. J. Exp. Med. 177, 457–463 (1993).

    Article  CAS  Google Scholar 

  25. Kuchroo, V., Umetsu, D., DeKruyff, R. & Freeman, G. The TIM gene family: emerging roles in immunity and disease. Nat. Rev. Immunol. 3, 454–462 (2003).

    Article  CAS  Google Scholar 

  26. Greenwald, R., Boussiotis, V., Lorsbach, R., Abbas, A. & Sharpe, A. CTLA-4 regulates induction of anergy in vivo. Immunity 14, 145–155 (2001).

    Article  CAS  Google Scholar 

  27. Ueda, H. et al. Association of the T-cell regulatory gene CTLA4 with susceptibility to autoimmune disease. Nature 423, 506–511 (2003).

    Article  CAS  Google Scholar 

  28. Thompson, P., Lu, J. & Kaplan, G. The Cys-rich region of hepatitis A virus cellular receptor 1 is required for binding of hepatitis A virus and protective monoclonal antibody 190/4. J. Virol. 72, 3751–3761 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Silberstein, E., Dveksler, G. & Kaplan, G. Neutralization of hepatitis A virus (HAV) by an immunoadhesin containing the cysteine-rich region of HAV cellular receptor-1. J. Virol. 75, 717–725 (2001).

    Article  CAS  Google Scholar 

  30. Xing, L. et al. Distinct cellular receptor interactions in poliovirus and rhinoviruses. EMBO J. 19, 1207–1216 (2000).

    Article  CAS  Google Scholar 

  31. Kaplan, G. et al. Identification of a surface glycoprotein on African green monkey kidney cells as a receptor for hepatitis A virus. EMBO J. 15, 4282–4296 (1996).

    Article  CAS  Google Scholar 

  32. Jentoft, N. Why are proteins O-glycosylated? Trends Biochem. Sci. 15, 291–294 (1990).

    Article  CAS  Google Scholar 

  33. Briskin, M., McEvoy, L. & Butcher, E. MAdCAM-1 has homology to immunoglobulin and mucin-like adhesion receptors and to IgA1. Nature 363, 461–464 (1993).

    Article  CAS  Google Scholar 

  34. Kovac, Z. & Schwartz, R. The molecular basis of the requirement for antigen processing of pigeon cytochrome c prior to T cell activation. J. Immunol. 134, 3233–3240 (1985).

    CAS  PubMed  Google Scholar 

  35. Matis, L. et al. Clonal analysis of the major histocompatibility complex restriction and the fine specificity of antigen recognition in the T cell proliferative response to cytochrome C. J. Immunol. 130, 1527–1535 (1983).

    CAS  PubMed  Google Scholar 

  36. Nicholson, L., Murtaza, A., Hafler, B., Sette, A. & Kuchroo, V. A T cell receptor antagonist peptide induces T cells that mediate bystander suppression and prevent autoimmune encephalomyelitis induced with multiple myelin antigens. Proc. Natl. Acad. Sci. USA 94, 9279–9284 (1997).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank L. Monney and A. Ryu for help with the initial studies of characterizing Tim-3–Ig fusion protein, and R. McGilp for flow cytometry sorting. Supported by the National Multiple Sclerosis Society (RG-2571-D-9 and FG-1478-A-1) and the National Institutes of Health (1RO1NS045937-01, 2R01NS35685-06, 2R37NS30843-11, 1RO1AI44880-03, 2P01AI39671-07, 1PO1NS38037-04 and 1F31GM20927-01).

Author information

Authors and Affiliations

  1. Department of Neurology, Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, 02115, Massachusetts, USA

    Catherine A Sabatos, Sumone Chakravarti, Eugene Cha, Anna Schubart & Vijay K Kuchroo

  2. Division of Immunology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, 02215, Massachusetts, USA

    Alberto Sánchez-Fueyo, Xin Xiao Zheng & Terry B Strom

  3. Inflammation Department, Experimental Medicine Division, Millennium Pharmaceuticals, Cambridge, 02139, Massachusetts, USA

    Anthony J Coyle

  4. Department of Medical Oncology, Dana-Farber Cancer Institute and Department of Medicine, Harvard Medical School, Boston, 02115, Massachusetts, USA

    Gordon J Freeman

Authors
  1. Catherine A Sabatos
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sumone Chakravarti
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Eugene Cha
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Anna Schubart
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Alberto Sánchez-Fueyo
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Xin Xiao Zheng
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Anthony J Coyle
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Terry B Strom
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Gordon J Freeman
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Vijay K Kuchroo
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Vijay K Kuchroo.

Ethics declarations

Competing interests

A.J.C. is employed by Millennium Pharmaceuticals, which holds the patent on TIM-3, and V.K.K. has a patent application pending related to Tim-3 and Tim-3L.

Supplementary information

Supplementary Fig. 1.

Administration of Tim-3-Ig does not induce hyperproliferation in SJL-Rag2-/- mice a) Spleen cells (5 x 105 cells/well) taken from immunized, fusion-protein treated SJL-Rag2-/- mice on day 10 were restimulated in vitro with 0-100 μg of PLP 139-151 peptide. Proliferation was measured after 48 h by 3[H]-thymidine incorporation in triplicate wells. (▴), PBS; (▪), hlgG; (●), fl-Tim-3-lg; and (○), s-Tim-3-lg-treated. Data shown for individual mice. (PDF 12 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Sabatos, C., Chakravarti, S., Cha, E. et al. Interaction of Tim-3 and Tim-3 ligand regulates T helper type 1 responses and induction of peripheral tolerance. Nat Immunol 4, 1102–1110 (2003). https://doi.org/10.1038/ni988

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ni988

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