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Activation of human CD4+ cells with CD3 and CD46 induces a T-regulatory cell 1 phenotype

Nature volume 421, pages 388–392 (2003)Cite this article

Abstract

The immune system must distinguish not only between self and non-self, but also between innocuous and pathological foreign antigens to prevent unnecessary or self-destructive immune responses. Unresponsiveness to harmless antigens is established through central and peripheral processes1. Whereas clonal deletion and anergy are mechanisms of peripheral tolerance2,3, active suppression by T-regulatory 1 (Tr1) cells has emerged as an essential factor in the control of autoreactive cells4. Tr1 cells are CD4+ T lymphocytes that are defined by their production of interleukin 10 (IL-10)5 and suppression of T-helper cells6; however, the physiological conditions underlying Tr1 differentiation are unknown. Here we show that co-engagement of CD3 and the complement regulator CD46 in the presence of IL-2 induces a Tr1-specific cytokine phenotype in human CD4+ T cells. These CD3/CD46-stimulated IL-10-producing CD4+ cells proliferate strongly, suppress activation of bystander T cells and acquire a memory phenotype. Our findings identify an endogenous receptor-mediated event that drives Tr1 differentiation and suggest that the complement system has a previously unappreciated role in T-cell-mediated immunity and tolerance.

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Figure 1: CD3/CD46 stimulation induces IL-10 production in human peripheral blood CD4+ T lymphocytes.
Figure 2: Sorted CD3+CD4+CD45RA+CD45RO+ T cells respond to primary and secondary activation with IL-10 production.
Figure 3: Characteristics of CD3/CD46-activated, sorted CD3+CD4+CD45RA+CD45RO+ T cells.
Figure 4: Suppressive and proliferative properties of CD3/CD46-activated CD4+ T cells.

References

  1. Van Parijs, A. & Abbas, A. K. Homeostasis and self-tolerance in the immune system: turning lymphocytes off. Science 280, 243–248 (1998)

    Article  ADS  CAS  PubMed  Google Scholar 

  2. Kappler, J. W., Roehm, N. & Marrack, P. T cell tolerance by clonal elimination in the thymus. Cell 49, 273–280 (1987)

    Article  CAS  PubMed  Google Scholar 

  3. Kisielow, P., Bluthmann, H., Staerz, U. D., Steinmetz, M. & von Boehmer, H. Tolerance in T-cell-receptor transgenic mice involves deletion of nonmature CD4+8+ thymocytes. Nature 333, 742–746 (1988)

    ADS  CAS  PubMed  Google Scholar 

  4. Sakaguchi, S. Regulatory T cells: key controllers of immunologic self-tolerance. Cell 101, 455–458 (2000)

    Article  CAS  PubMed  Google Scholar 

  5. Groux, H. et al. A CD4+ T-cell subset inhibits antigen-specific T-cell responses and prevents colitis. Nature 389, 737–742 (1997)

    Article  ADS  CAS  PubMed  Google Scholar 

  6. Roncarolo, M. G. & Levings, M. K. The role of different subsets of T regulatory cells in controlling autoimmunity. Curr. Opin. Immunol. 12, 676–683 (2000)

    Article  CAS  PubMed  Google Scholar 

  7. LeDouarin, N. et al. Evidence for a thymus-dependent form of tolerance that is not based on elimination or anergy of reactive T cells. Immunol. Rev. 149, 35–53 (1996)

    Article  CAS  Google Scholar 

  8. Shevach, E. M. Regulatory T cells in autoimmunity. Annu. Rev. Immunol. 18, 423–449 (2000)

    Article  CAS  PubMed  Google Scholar 

  9. Shevach, E. M. S. M. R., Piccirillo, C. A. & Thornton, A. M. Control of T-cell activation by CD4+CD25+ suppressor T cells. Immunol. Rev. 182, 58–67 (2001)

    Article  CAS  PubMed  Google Scholar 

  10. Chen, Y., Kuchroo, V. K., Inobe, J., Hafler, D. A. & Weiner, H. L. Regulatory T cell clones induced by oral tolerance: suppression of autoimmune encephalomyelitis. Science 265, 1237–1240 (1994)

    Article  ADS  CAS  PubMed  Google Scholar 

  11. Roncarolo, M. G., Bacchetta, R., Bordignon, C., Narula, S. & Levings, M. K. Type 1 regulatory cells. Immunol. Rev. 182, 68–79 (2001)

    Article  CAS  PubMed  Google Scholar 

  12. Barrat, F. J. et al. In vitro generation of interleukin 10-producing regulatory CD4+ T cells is induced by immunosuppressive drugs and inhibited by T helper type 1 (Th1)- and Th2-inducing cytokines. J. Exp. Med. 195, 603–616 (2002)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Cole, J. L., Housley, G. A. Jr, Dykman, T. R., MacDermott, R. P. & Atkinson, J. P. Identification of an additional class of C3-binding membrane proteins of human peripheral blood leukocytes and cell lines. Proc. Natl Acad. Sci. USA 82, 859–863 (1985)

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  14. Liszewski, M. K., Post, T. W. & Atkinson, J. P. Membrane cofactor protein (MCP or CD46): newest member of the regulators of complement activation gene cluster. Annu. Rev. Immunol. 9, 431–455 (1991)

    Article  CAS  PubMed  Google Scholar 

  15. Dorig, R. E., Marcil, A., Chopra, A. & Richardson, C. D. The human CD46 molecule is a receptor for measles virus (Edmonston strain). Cell 75, 295–305 (1993)

    Article  CAS  PubMed  Google Scholar 

  16. Naniche, D. et al. Human membrane cofactor protein (CD46) acts as a cellular receptor for measles virus. J. Virol. 67, 6025–6032 (1993)

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Santoro, F. et al. CD46 is a cellular receptor for human herpes virus 6. Cell 99, 817–827 (1999)

    Article  CAS  PubMed  Google Scholar 

  18. Okada, N., Liszewski, M. K., Atkinson, J. P. & Caparon, M. Membrane cofactor protein (MCP; CD46) is a keratinocyte receptor for the M protein of group A streptococcus. Proc. Natl Acad. Sci. USA 92, 2489–2493 (1995)

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  19. Kallstrom, H., Liszewski, M. K., Atkinson, J. P. & Jonsson, A.-B. Membrane cofactor protein (MCP or CD46) is a cellular pilus receptor for pathogenic Neisseria. Mol. Microbiol. 25, 639–647 (1997)

    Article  CAS  PubMed  Google Scholar 

  20. Karp, C. L. et al. Mechanism of suppression of cell-mediated immunity by measles virus. Science 273, 228–231 (1996)

    Article  ADS  CAS  PubMed  Google Scholar 

  21. Kallstrom, H., Islam, M. S., Berggren, P. O. & Jonsson, A. B. Cell signaling by the type IV pili of pathogenic Neisseria. J. Biol. Chem. 273, 21777–21782 (1998)

    Article  CAS  PubMed  Google Scholar 

  22. Astier, A., Trescol-Biemont, M.-C., Azocar, O., Lamouille, B. & Rabourdin-Combe, C. Cutting edge: CD46, a new costimulatory molecular for T cells, that induces p120CBL and LAT phosphorylation. J. Immunol. 164, 6091–6095 (2000)

    Article  CAS  PubMed  Google Scholar 

  23. Wang, G., Liszewski, M. K., Chan, A. C. & Atkinson, J. P. Membrane cofactor protein (MCP; CD46): isoform-specific tyrosine phosphorylation. J. Immunol. 164, 1839–1846 (2000)

    Article  CAS  PubMed  Google Scholar 

  24. Marie, J. et al. Linking innate and acquired immunity: divergent role of CD46 cytoplasmic domains in T cell-induced inflammation. Nature Immunol. 3, 659–666 (2002)

    Article  CAS  Google Scholar 

  25. Nielsen, C. H., Fischer, E. M. & Leslie, R. G. The role of complement in the acquired immune response. Immunology 100, 4–12 (2000)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Dempsey, P. W., Allison, M. E., Akkaraju, S., Goodnow, C. C. & Fearon, D. T. C3d of complement as a molecular adjuvant: bridging innate and acquired immunity. Science 271, 348–350 (1996)

    Article  ADS  CAS  PubMed  Google Scholar 

  27. Prodeus, A. P. et al. A critical role for complement in maintenance of self-tolerance. Immunity 9, 721–731 (1998)

    Article  CAS  PubMed  Google Scholar 

  28. McGuirk, P. & Mills, K. H. G. Pathogen-specific regulatory T cells provoke a shift in the Th1/Th2 paradigm in immunity to infectious diseases. Trends. Immunol. 23, 450–455 (2002)

    Article  CAS  PubMed  Google Scholar 

  29. Liszewski, M. K. et al. Dissecting sites important for complement regulatory activity in membrane cofactor protein (MCP; CD46). J. Biol. Chem. 275, 37692–37701 (2001)

    Article  Google Scholar 

  30. Krych-Goldberg, M. et al. Decay accelerating activity of complement receptor type 1 (CD35). J. Biol. Chem. 274, 31160–31168 (1999)

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank H. Molina, K. Liszewski, L. S. Wen and M. Denny for comments on the manuscript, and the immunology community at Washington University School of Medicine for discussions.

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  1. John P. Atkinson

    Present address: School of Medicine, 660 South Euclid Avenue, Campus Box 8045, St Louis, Missouri, 63110, USA

Authors and Affiliations

  1. Division of Rheumatology, Washington University School of Medicine, St Louis, Missouri, 63110, USA

    Claudia Kemper, Kelly A. Brett & John P. Atkinson

  2. Genentech, Inc., San Francisco, California, 94080, USA

    Andrew C. Chan

  3. Department of Internal Medicine, Washington University School of Medicine, St Louis, Missouri, 63110, USA

    Jonathan M. Green

  4. Graduate Program in Immunology, Washington University School of Medicine, St Louis, Missouri, 63110, USA

    Kelly A. Brett

  5. Division of Pathology and Immunology, Washington University School of Medicine, and Howard Hughes Medical Institute, St Louis, Missouri, 63110, USA

    Kenneth M. Murphy

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Correspondence to John P. Atkinson.

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Kemper, C., Chan, A., Green, J. et al. Activation of human CD4+ cells with CD3 and CD46 induces a T-regulatory cell 1 phenotype. Nature 421, 388–392 (2003). https://doi.org/10.1038/nature01315

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