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.
Access optionsAccess options
Subscribe to Journal
Get full journal access for 1 year
only $3.90 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Van Parijs, A. & Abbas, A. K. Homeostasis and self-tolerance in the immune system: turning lymphocytes off. Science 280, 243–248 (1998)
Kappler, J. W., Roehm, N. & Marrack, P. T cell tolerance by clonal elimination in the thymus. Cell 49, 273–280 (1987)
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)
Sakaguchi, S. Regulatory T cells: key controllers of immunologic self-tolerance. Cell 101, 455–458 (2000)
Groux, H. et al. A CD4+ T-cell subset inhibits antigen-specific T-cell responses and prevents colitis. Nature 389, 737–742 (1997)
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)
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)
Shevach, E. M. Regulatory T cells in autoimmunity. Annu. Rev. Immunol. 18, 423–449 (2000)
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)
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)
Roncarolo, M. G., Bacchetta, R., Bordignon, C., Narula, S. & Levings, M. K. Type 1 regulatory cells. Immunol. Rev. 182, 68–79 (2001)
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)
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)
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)
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)
Naniche, D. et al. Human membrane cofactor protein (CD46) acts as a cellular receptor for measles virus. J. Virol. 67, 6025–6032 (1993)
Santoro, F. et al. CD46 is a cellular receptor for human herpes virus 6. Cell 99, 817–827 (1999)
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)
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)
Karp, C. L. et al. Mechanism of suppression of cell-mediated immunity by measles virus. Science 273, 228–231 (1996)
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)
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)
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)
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)
Nielsen, C. H., Fischer, E. M. & Leslie, R. G. The role of complement in the acquired immune response. Immunology 100, 4–12 (2000)
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)
Prodeus, A. P. et al. A critical role for complement in maintenance of self-tolerance. Immunity 9, 721–731 (1998)
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)
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)
Krych-Goldberg, M. et al. Decay accelerating activity of complement receptor type 1 (CD35). J. Biol. Chem. 274, 31160–31168 (1999)
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.
The authors declare that they have no competing financial interests.
About this article
Seminars in Cell & Developmental Biology (2019)
Angiotensin AT2 receptor–induced interleukin-10 attenuates neuromyelitis optica spectrum disorder–like pathology
Multiple Sclerosis Journal (2019)
Immunology & Cell Biology (2019)
The Role of Membrane Bound Complement Regulatory Proteins in Tumor Development and Cancer Immunotherapy
Frontiers in Immunology (2019)
Molecular Immunology (2019)