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T cell regulation mediated by interaction of soluble CD52 with the inhibitory receptor Siglec-10

Abstract

Functionally diverse T cell populations interact to maintain homeostasis of the immune system. We found that human and mouse antigen-activated T cells with high expression of the lymphocyte surface marker CD52 suppressed other T cells. CD52hiCD4+ T cells were distinct from CD4+CD25+Foxp3+ regulatory T cells. Their suppression was mediated by soluble CD52 released by phospholipase C. Soluble CD52 bound to the inhibitory receptor Siglec-10 and impaired phosphorylation of the T cell receptor–associated kinases Lck and Zap70 and T cell activation. Humans with type 1 diabetes had a lower frequency and diminished function of CD52hiCD4+ T cells responsive to the autoantigen GAD65. In diabetes-prone mice of the nonobese diabetic (NOD) strain, transfer of lymphocyte populations depleted of CD52hi cells resulted in a substantially accelerated onset of diabetes. Our studies identify a ligand-receptor mechanism of T cell regulation that may protect humans and mice from autoimmune disease.

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Figure 1: CD52 expression distinguishes suppressor CD4+ T cells in healthy people.
Figure 2: CD52hi T cells are distinct from CD4+CD25+ Treg cells.
Figure 3: GAD65-activated CD52hi T cells are impaired in type 1 diabetes.
Figure 4: CD52hi T cells retard the development of diabetes in NOD mice.
Figure 5: Soluble CD52 mediates suppression by CD52hi T cells.
Figure 6: Soluble CD52 inhibits activation via the TCR.
Figure 7: Soluble CD52 binds via its glycan moiety to Siglec-10.

References

  1. Hori, S., Nomura, T. & Sakaguchi, S. Control of regulatory T cell development by the transcription factor Foxp3. Science 299, 1057–1061 (2003).

    CAS  PubMed  Article  Google Scholar 

  2. Fontenot, J.D., Gavin, M.A. & Rudensky, A.Y. Foxp3 programs the development and function of CD4+CD25+ regulatory T cells. Nat. Immunol. 4, 330–336 (2003).

    CAS  PubMed  Google Scholar 

  3. Shevach, E.M. From vanilla to 28 flavors: multiple varieties of T regulatory cells. Immunity 25, 195–201 (2006).

    CAS  PubMed  Article  Google Scholar 

  4. Corthay, A. How do regulatory T cells work? Scand. J. Immunol. 70, 326–336 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  5. Long, S.A. & Buckner, J.H. CD4+FOXP3+ T regulatory cells in human autoimmunity: more than a numbers game. J. Immunol. 187, 2061–2066 (2011).

    CAS  PubMed  Article  Google Scholar 

  6. Gavin, M.A. et al. Single-cell analysis of normal and FOXP3-mutant human T cells: FOXP3 expression without regulatory T cell development. Proc. Natl. Acad. Sci. USA 103, 6659–6664 (2006).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  7. Wang, J., Ioan-Facsinay, A., van der Voort, E.I., Huizinga, T.W. & Toes, R.E. Transient expression of FOXP3 in human activated nonregulatory CD4+ T cells. Eur. J. Immunol. 37, 129–138 (2007).

    CAS  PubMed  Article  Google Scholar 

  8. Roncarolo, M.G. & Gregori, S. Is FOXP3 a bona fide marker for human regulatory T cells? Eur. J. Immunol. 38, 925–927 (2008).

    CAS  PubMed  Article  Google Scholar 

  9. Miyara, M. et al. Functional delineation and differentiation dynamics of human CD4+ T cells expressing the FoxP3 transcription factor. Immunity 30, 899–911 (2009).

    CAS  Article  PubMed  Google Scholar 

  10. Liu, W. et al. CD127 expression inversely correlates with FoxP3 and suppressive function of human CD4+ T reg cells. J. Exp. Med. 203, 1701–1711 (2006).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  11. Seddiki, N. et al. Expression of interleukin (IL)-2 and IL-7 receptors discriminates between human regulatory and activated T cells. J. Exp. Med. 203, 1693–1700 (2006).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  12. von Herrath, M.G. & Harrison, L.C. Antigen-induced regulatory T cells in autoimmunity. Nat. Rev. Immunol. 3, 223–232 (2003).

    CAS  PubMed  Article  Google Scholar 

  13. Harrison, L.C. Vaccination against self to prevent autoimmune disease: the type 1 diabetes model. Immunol. Cell Biol. 86, 139–145 (2008).

    CAS  PubMed  Article  Google Scholar 

  14. Dromey, J.A. et al. Generation and expansion of regulatory human CD4+ T-cell clones specific for pancreatic islet autoantigens. J. Autoimmun. 36, 47–55 (2011).

    CAS  PubMed  Article  Google Scholar 

  15. Xia, M.Q., Tone, M., Packman, L., Hale, G. & Waldmann, H. Characterization of the CAMPATH-1 (CDw52) antigen: biochemical analysis and cDNA cloning reveal an unusually small peptide backbone. Eur. J. Immunol. 21, 1677–1684 (1991).

    CAS  PubMed  Article  Google Scholar 

  16. Hale, G. Cd52 (Campath1). J. Biol. Regul. Homeost. Agents 15, 386–391 (2001).

    CAS  PubMed  Google Scholar 

  17. Baron, U. et al. DNA methylation in the human FOXP3 locus discriminates regulatory T cells from FOXP3+ conventional T cells. Eur. J. Immunol. 37, 2378–2389 (2007).

    CAS  PubMed  Article  Google Scholar 

  18. Tone, M. et al. Structure and chromosomal location of mouse and human CD52 genes. Biochim. Biophys. Acta 1446, 334–340 (1999).

    CAS  PubMed  Article  Google Scholar 

  19. Chen, G.Y., Tang, J., Zheng, P. & Liu, Y. CD24 and Siglec-10 selectively repress tissue damage-induced immune responses. Science 323, 1722–1725 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  20. Adorini, L., Gregori, S. & Harrison, L.C. Understanding autoimmune diabetes: insights from mouse models. Trends Mol. Med. 8, 31–38 (2002).

    CAS  PubMed  Article  Google Scholar 

  21. Augstein, P. et al. Beta-cell apoptosis in an accelerated model of autoimmune diabetes. Mol. Med. 4, 495–501 (1998).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  22. Shevach, E.M. Mechanisms of foxp3+ T regulatory cell-mediated suppression. Immunity 30, 636–645 (2009).

    CAS  Article  PubMed  Google Scholar 

  23. Sakaguchi, S., Wing, K., Onishi, Y., Prieto-Martin, P. & Yamaguchi, T. Regulatory T cells: how do they suppress immune responses? Int. Immunol. 21, 1105–1111 (2009).

    CAS  PubMed  Article  Google Scholar 

  24. Collison, L.W. et al. The inhibitory cytokine IL-35 contributes to regulatory T-cell function. Nature 450, 566–569 (2007).

    CAS  Article  PubMed  Google Scholar 

  25. Treumann, A., Lifely, M.R., Schneider, P. & Ferguson, M.A. Primary structure of CD52. J. Biol. Chem. 270, 6088–6099 (1995).

    CAS  PubMed  Article  Google Scholar 

  26. Mustelin, T. & Tasken, K. Positive and negative regulation of T-cell activation through kinases and phosphatases. Biochem. J. 371, 15–27 (2003).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  27. Varki, A. & Angata, T. Siglecs–the major subfamily of I-type lectins. Glycobiology 16, 1–27 (2006).

    Article  Google Scholar 

  28. Crocker, P.R., Paulson, J.C. & Varki, A. Siglecs and their roles in the immune system. Nat. Rev. Immunol. 7, 255–266 (2007).

    CAS  PubMed  Article  Google Scholar 

  29. Nguyen, D.H., Hutado-Ziola, N., Gagneux, P. & Varki, A. Loss of Siglec expression on T lymphocytes during human evolution. Proc. Natl. Acad. Sci. USA 103, 7765–7770 (2006).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  30. MacDonald, H.R., Bron, C., Rousseaux, M., Horvath, C. & Cerottini, J.C. Production and characterization of monoclonal anti-Thy-1 antibodies that stimulate lymphokine production by cytolytic T cell clones. Eur. J. Immunol. 15, 495–501 (1985).

    CAS  PubMed  Article  Google Scholar 

  31. Korty, P.E., Brando, C. & Shevach, E.M. CD59 functions as a signal-transducing molecule for human T cell activation. J. Immunol. 146, 4092–4098 (1991).

    CAS  PubMed  Google Scholar 

  32. Thompson, L.F., Ruedi, J.M., Glass, A., Low, M.G. & Lucas, A.H. Antibodies to 5′-nucleotidase (CD73), a glycosyl-phosphatidylinositol-anchored protein, cause human peripheral blood T cells to proliferate. J. Immunol. 143, 1815–1821 (1989).

    CAS  PubMed  Google Scholar 

  33. Rowan, W.C., Hale, G., Tite, J.P. & Brett, S.J. Cross-linking of the CAMPATH-1 antigen (CD52) triggers activation of normal human T lymphocytes. Int. Immunol. 7, 69–77 (1995).

    CAS  PubMed  Article  Google Scholar 

  34. Watanabe, T. et al. CD52 is a novel costimulatory molecule for induction of CD4+ regulatory T cells. Clin. Immunol. 120, 247–259 (2006).

    CAS  PubMed  Article  Google Scholar 

  35. Kubota, H. et al. Identification and gene cloning of a new phosphatidylinositol-linked antigen expressed on mature lymphocytes. Down-regulation by lymphocyte activation. J. Immunol. 145, 3924–3931 (1990).

    CAS  PubMed  Google Scholar 

  36. Haaland, R.E., Yu, W. & Rice, A.P. Identification of LKLF-regulated genes in quiescent CD4+ T lymphocytes. Mol. Immunol. 42, 627–641 (2005).

    CAS  PubMed  Article  Google Scholar 

  37. Varki, A. Natural ligands for CD33-related Siglecs? Glycobiology 19, 810–812 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  38. Clatworthy, M.R., Wallin, E.F. & Jayne, D.R. Anti-glomerular basement membrane disease after alemtuzumab. N. Engl. J. Med. 359, 768–769 (2008).

    CAS  PubMed  Article  Google Scholar 

  39. Coles, A.J. et al. Pulsed monoclonal antibody treatment and autoimmune thyroid disease in multiple sclerosis. Lancet 354, 1691–1695 (1999).

    CAS  PubMed  Article  Google Scholar 

  40. Coles, A.J. et al. Alemtuzumab vs. interferon β-1a in early multiple sclerosis. N. Engl. J. Med. 359, 1786–1801 (2008).

    PubMed  Article  Google Scholar 

  41. Cossburn, M. et al. Autoimmune disease after alemtuzumab treatment for multiple sclerosis in a multicenter cohort. Neurology 77, 573–579 (2011).

    CAS  PubMed  Article  Google Scholar 

  42. Xia, M.-Q. et al. Structure of the CAMPATH-1 antigen, a glycosylphosphatidylinositol anchored glycoprotein which is an exceptionally good target for complement lysis. Biochem. J. 293, 633–640 (1993).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  43. Belov, L., Huang, P., Barber, N., Mulligan, S.P. & Christopherson, R.I. Identification of repertoires of surface antigens on leukemias using an antibody microarray. Proteomics 3, 2147–2154 (2003).

    CAS  PubMed  Article  Google Scholar 

  44. Armour, K.L., van de Winkel, J.G., Williamson, L.M. & Clark, M.R. Differential binding to human FcγRIIa and FcγRIIb receptors by human IgG wildtype and mutant antibodies. Mol. Immunol. 40, 585–593 (2003).

    CAS  PubMed  Article  Google Scholar 

  45. Schmidt, T.G. & Skerra, A. The Strep-tag system for one-step purification and high-affinity detection or capturing of proteins. Nat. Protoc. 2, 1528–1535 (2007).

    CAS  PubMed  Article  Google Scholar 

  46. Herold, M.J., van den Brandt, J., Seibler, J. & Reichardt, H.M. Inducible and reversible gene silencing by stable integration of an shRNA-encoding lentivirus in transgenic rats. Proc. Natl. Acad. Sci. USA 105, 18507–18512 (2008).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We thank M.R. Clark (University of Cambridge) for DNA encoding immunoglobulin G1 Fc; and L. Belov, K. Ngui, A. Neale, J. Butler, D. Mittag, M. Herold, N. Stone, N. Lynch, H. Thomas, S. Finch and T. Adams for technical assistance and advice. Supported by the National Health and Medical Research Council of Australia (637301 to L.C.H. and 516700) and facilitated by the Victorian State Government Operational Infrastructure Support and Australian Government National Health and Medical Research Council Independent Research Institutes Infrastructure Support Scheme.

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L.C.H., J.A.D., E.B.-S., Y.Z., S.R., B.-H.L., J.Q. and R.M.B. designed the studies; L.C.H. drafted the manuscript; E.B.-S., Y.Z. and R.M.B. assisted in redrafting the manuscript; and all authors did the molecular and cellular studies, analyzed the data and discussed and commented on the manuscript.

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Correspondence to Leonard C Harrison.

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Bandala-Sanchez, E., Zhang, Y., Reinwald, S. et al. T cell regulation mediated by interaction of soluble CD52 with the inhibitory receptor Siglec-10. Nat Immunol 14, 741–748 (2013). https://doi.org/10.1038/ni.2610

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