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Complement regulator CD46 temporally regulates cytokine production by conventional and unconventional T cells

Nature Immunology volume 11, pages 862–871 (2010)Cite this article

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Abstract

In this study we demonstrate a new form of immunoregulation: engagement on CD4+ T cells of the complement regulator CD46 promoted the effector potential of T helper type 1 cells (TH1 cells), but as interleukin 2 (IL-2) accumulated, it switched cells toward a regulatory phenotype, attenuating IL-2 production via the transcriptional regulator ICER/CREM and upregulating IL-10 after interaction of the CD46 tail with the serine-threonine kinase SPAK. Activated CD4+ T cells produced CD46 ligands, and blocking CD46 inhibited IL-10 production. Furthermore, CD4+ T cells in rheumatoid arthritis failed to switch, consequently producing excessive interferon-γ (IFN-γ). Finally, γδ T cells, which rarely produce IL-10, expressed an alternative CD46 isoform and were unable to switch. Nonetheless, coengagement of T cell antigen receptor (TCR) γδ and CD46 suppressed effector cytokine production, establishing that CD46 uses distinct mechanisms to regulate different T cell subsets during an immune response.

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Figure 1: IL-2 regulates TH1 versus Tr1 effector function in CD4+ T cells activated with anti-CD3 and anti-CD46.
Figure 2: CD46–IL-2 signals induce a switch from a TH1 phenotype to a suppressive Tr1 phenotype in CD4+ T cells.
Figure 3: CD46-mediated signals contribute to the regulation of IL-2 expression by CD4+ T cells.
Figure 4: The intracellular CYT-1 domain of CD46 and SPAK are required for IL-10 production in CD4+ T cells.
Figure 5: CD46 directly regulates γδ T cell function.
Figure 6: CD4+ T cells from patients with rheumatoid arthritis are defective in the IFN-γ–IL-10 switch induced by anti-CD3 and anti-CD46.
Figure 7: Engagement of CD46 by locally produced C3b drives IL-10 expression in CD4+ T cells stimulated with anti-CD3 and anti-CD28.

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Acknowledgements

We thank H. Jomaa (Justus-Liebig-Universität) for HMBPP; K. Murphy for advice and discussions; and C. Hawrylowicz for help with manuscript revision. Supported by the American Asthma Foundation (formerly Sandler Program for Asthma Research; J.P.A. and C.K.), the Wellcome Trust (A.H. and A.R.), Cancer Research UK (A.H. and P.V.), the US National Institutes of Health (AI037618 to J.P.A.), the Medical Research Council Centre for Transplantation, Guy's Hospital, King's College (G.L. and C.K.) and the Department of Health, National Institute for Health Research comprehensive Biomedical Research Centre award to Guy's & St. Thomas' NHS Foundation Trust in partnership with King's College London and King's College Hospital NHS Foundation Trust (G.L.F., A.H and C.K).

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  1. John Cardone and Gaelle Le Friec: These authors contributed equally to this study.

Authors and Affiliations

  1. Division of Immunology, Infection and Inflammatory Diseases, King's College London, Medical Research Council Centre for Transplantation, Guy's Hospital, London, UK

    John Cardone, Gaelle Le Friec, Ian Jackson, Tesha Suddason, Graham Lord, Adrian Hayday & Claudia Kemper

  2. London Research Institute, Cancer Research UK, London, UK

    Pierre Vantourout, Andrew Roberts & Adrian Hayday

  3. Peter Gorer Department of Immunobiology, King's College London, Guy's Hospital, London, UK

    Pierre Vantourout, Andrew Roberts & Adrian Hayday

  4. Department of Medicine, Division of Immunology and Pathology, Washington University School of Medicine, St. Louis, Missouri, USA

    Anja Fuchs

  5. Biomedical Research Centre, King's Health Partners, Guy's Hospital, London, UK

    Ian Jackson, Tesha Suddason, Graham Lord, Andrew Cope & Adrian Hayday

  6. Department of Medicine, Division of Rheumatology, Washington University School of Medicine, St. Louis, Missouri, USA

    John P Atkinson

  7. Academic Department of Rheumatology, King's College London, London, UK

    Andrew Cope

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Contributions

J.C., G.L.F., P.V., A.R., A.F., I.J., T.S. and C.K. did the experiments, discussed data and corrected the manuscript; G.L. provided financial support for I.J. and T.S. and aided in data discussion; J.P.A. provided reagents, helped design experiments involving CD46-mediated signaling events, assisted in interpreting the data and revised the manuscript; A.C. designed experiments involving patients with rheumatoid arthritis and provided patient samples; A.H. designed experiments with γδ T cells and revised the manuscript; and C.K. designed the study and wrote the manuscript.

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Correspondence to Claudia Kemper.

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Cardone, J., Le Friec, G., Vantourout, P. et al. Complement regulator CD46 temporally regulates cytokine production by conventional and unconventional T cells. Nat Immunol 11, 862–871 (2010). https://doi.org/10.1038/ni.1917

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