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The CD46-Jagged1 interaction is critical for human TH1 immunity

Nature Immunology volume 13, pages 1213–1221 (2012)Cite this article

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Abstract

CD46 is a complement regulator with important roles related to the immune response. CD46 functions as a pathogen receptor and is a potent costimulator for the induction of interferon-γ (IFN-γ)-secreting effector T helper type 1 (TH1) cells and their subsequent switch into interleukin 10 (IL-10)-producing regulatory T cells. Here we identified the Notch family member Jagged1 as a physiological ligand for CD46. Furthermore, we found that CD46 regulated the expression of Notch receptors and ligands during T cell activation and that disturbance of the CD46-Notch crosstalk impeded induction of IFN-γ and switching to IL-10. Notably, CD4+ T cells from CD46-deficient patients and patients with hypomorphic mutations in the gene encoding Jagged1 (Alagille syndrome) failed to mount appropriate TH1 responses in vitro and in vivo, which suggested that CD46-Jagged1 crosstalk is responsible for the recurrent infections in subpopulations of these patients.

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Figure 1: Jagged1 is a ligand for CD46.
Figure 2: Jagged1 binds to CCP1 and CCP2 of CD46.
Figure 3: CD46 regulates the expression of Notch receptors and ligands on human CD4+ T cells.
Figure 4: Undisturbed crosstalk by the CD46 and Notch system is required for normal switching of human TH1 cells from IFN-γ to IL-10.
Figure 5: T cells from CD46-deficient patients have defective in vitro TH1 induction.
Figure 6: T cells from patients with Alagille syndrome have defective in vitro TH1 induction.

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References

  1. 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 

  2. Cattaneo, R. Four viruses, two bacteria, and one receptor: membrane cofactor protein (CD46) as pathogens' magnet. J. Virol. 78, 4385–4388 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  4. Cardone, J. et al. Complement regulator CD46 temporally regulates cytokine production by conventional and unconventional T cells. Nat. Immunol. 11, 862–871 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Cope, A., Le Friec, G., Cardone, J. & Kemper, C. The Th1 life cycle: molecular control of IFN-γ to IL-10 switching. Trends Immunol. 32, 278–286 (2011).

    Article  CAS  PubMed  Google Scholar 

  6. Casasnovas, J.M., Larvie, M. & Stehle, T. Crystal structure of two CD46 domains reveals an extended measles virus-binding surface. EMBO J. 18, 2911–2922 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Arnberg, N. Adenovirus receptors: implications for tropism, treatment and targeting. Rev. Med. Virol. 19, 165–178 (2009).

    Article  CAS  PubMed  Google Scholar 

  8. Riley, R.C., Tannenbaum, P.L., Abbott, D.H. & Atkinson, J.P. Cutting edge: inhibiting measles virus infection but promoting reproduction: an explanation for splicing and tissue-specific expression of CD46. J. Immunol. 169, 5405–5409 (2002).

    Article  CAS  PubMed  Google Scholar 

  9. Amsen, D., Antov, A. & Flavell, R.A. The different faces of Notch in T-helper-cell differentiation. Nat. Rev. Immunol. 9, 116–124 (2009).

    Article  CAS  PubMed  Google Scholar 

  10. Fremeaux-Bacchi, V. et al. Genetic and functional analyses of membrane cofactor protein (CD46) mutations in atypical hemolytic uremic syndrome. J. Am. Soc. Nephrol. 17, 2017–2025 (2006).

    Article  CAS  PubMed  Google Scholar 

  11. Couzi, L. et al. Inherited deficiency of membrane cofactor protein expression and varying manifestations of recurrent atypical hemolytic uremic syndrome in a sibling pair. Am. J. Kidney Dis. 52, e5–e9 (2008).

    Article  PubMed  Google Scholar 

  12. Vajro, P., Ferrante, L. & Paolella, G. Alagille syndrome: An overview. Clin. Res. Hepatol. Gastroenterol. 36, 275–277 (2012).

    Article  PubMed  Google Scholar 

  13. Cordle, J. et al. A conserved face of the Jagged/Serrate DSL domain is involved in Notch trans-activation and cis-inhibition. Nat. Struct. Mol. Biol. 15, 849–857 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Greig, J.A. et al. Influence of coagulation factor x on in vitro and in vivo gene delivery by adenovirus (Ad) 5, Ad35, and chimeric Ad5/Ad35 vectors. Mol. Ther. 17, 1683–1691 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Tsujimura, A. et al. Molecular cloning of a murine homologue of membrane cofactor protein (CD46): preferential expression in testicular germ cells. Biochem. J. 330, 163–168 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Fernández-Centeno, E., de Ojeda, G., Rojo, J.M. & Portoles, P. Crry/p65, a membrane complement regulatory protein, has costimulatory properties on mouse T cells. J. Immunol. 164, 4533–4542 (2000).

    Article  PubMed  Google Scholar 

  17. Grzesiek, S. & Bax, A. Amino acid type determination in the sequential assignment procedure of uniformly 13C/15N-enriched proteins. J. Biomol. NMR 3, 185–204 (1993).

    CAS  PubMed  Google Scholar 

  18. Kemper, C. & Atkinson, J.P. T-cell regulation: with complements from innate immunity. Nat. Rev. Immunol. 7, 9–18 (2007).

    Article  CAS  PubMed  Google Scholar 

  19. Kemper, C. et al. Activation of human CD4+ cells with CD3 and CD46 induces a T-regulatory cell 1 phenotype. Nature 421, 388–392 (2003).

    Article  CAS  PubMed  Google Scholar 

  20. Kopan, R. & Ilagan, M.X. The canonical Notch signaling pathway: unfolding the activation mechanism. Cell 137, 216–233 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Rutz, S. et al. Notch regulates IL-10 production by T helper 1 cells. Proc. Natl. Acad. Sci. USA 105, 3497–3502 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  22. Ni Choileain, S. et al. The dynamic processing of CD46 intracellular domains provides a molecular rheostat for T cell activation. PLoS ONE 6, e16287 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Cardone, J., Al-Shouli, S. & Kemper, C. A novel role for CD46 in wound repair in. Front Immun. 2, 28 (2011).

    Article  Google Scholar 

  24. Fang, C.J. et al. Membrane cofactor protein mutations in atypical hemolytic uremic syndrome (aHUS), fatal Stx-HUS, C3 glomerulonephritis, and the HELLP syndrome. Blood 111, 624–632 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Romagnani, S. Th1/Th2 cells. Inflamm. Bowel Dis. 5, 285–294 (1999).

    Article  CAS  PubMed  Google Scholar 

  26. Fuchs, A., Atkinson, J.P., Fremeaux-Bacchi, V. & Kemper, C. CD46-induced human Treg enhance B-cell responses. Eur. J. Immunol. 39, 3097–3109 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Liao, W., Lin, J.X. & Leonard, W.J. IL-2 family cytokines: new insights into the complex roles of IL-2 as a broad regulator of T helper cell differentiation. Curr. Opin. Immunol. 23, 598–604 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Nervi, B. et al. Factors affecting human T cell engraftment, trafficking, and associated xenogeneic graft-vs-host disease in NOD/SCID beta2mnull mice. Exp. Hematol. 35, 1823–1838 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Liu, J., Sato, C., Cerletti, M. & Wagers, A. Notch signaling in the regulation of stem cell self-renewal and differentiation. Curr. Top. Dev. Biol. 92, 367–409 (2010).

    Article  CAS  PubMed  Google Scholar 

  30. Oda, T. et al. Mutations in the human Jagged1 gene are responsible for Alagille syndrome. Nat. Genet. 16, 235–242 (1997).

    Article  CAS  PubMed  Google Scholar 

  31. Quiros-Tejeira, R.E. et al. Variable morbidity in Alagille syndrome: a review of 43 cases. J. Pediatr. Gastroenterol. Nutr. 29, 431–437 (1999).

    Article  CAS  PubMed  Google Scholar 

  32. Robinson, M. et al. An analysis of the normal ranges of lymphocyte subpopulations in children aged 5–13 years. Eur. J. Pediatr. 155, 535–539 (1996).

    CAS  PubMed  Google Scholar 

  33. Bhavsar, P.J., Infante, E., Khwaja, A. & Ridley, A.J. Analysis of Rho GTPase expression in T-ALL identifies RhoU as a target for Notch involved in T-ALL cell migration. Oncogene (2012).

  34. del Álamo, D., Rouault, H. & Schweisguth, F. Mechanism and significance of cis-inhibition in Notch signalling. Curr. Biol. 21, R40–R47 (2011).

    Article  CAS  PubMed  Google Scholar 

  35. Alford, S.K., Longmore, G.D., Stenson, W.F. & Kemper, C. CD46-induced immunomodulatory CD4+ T cells express the adhesion molecule and chemokine receptor pattern of intestinal T cells. J. Immunol. 181, 2544–2555 (2008).

    Article  CAS  PubMed  Google Scholar 

  36. Bikker, A., Hack, C.E., Lafeber, F.P. & van Roon, J.A. Interleukin-7: a key mediator in T cell-driven autoimmunity, inflammation, and tissue destruction. Curr. Pharm. Des. 18, 2347–2356 (2012).

    Article  CAS  PubMed  Google Scholar 

  37. Gregory, S.G. et al. Interleukin 7 receptor α chain (IL7R) shows allelic and functional association with multiple sclerosis. Nat. Genet. 39, 1083–1091 (2007).

    Article  CAS  PubMed  Google Scholar 

  38. Hafler, D.A. et al. Risk alleles for multiple sclerosis identified by a genomewide study. N. Engl. J. Med. 357, 851–862 (2007).

    Article  CAS  PubMed  Google Scholar 

  39. Astier, A.L., Meiffren, G., Freeman, S. & Hafler, D.A. Alterations in CD46-mediated Tr1 regulatory T cells in patients with multiple sclerosis. J. Clin. Invest. 116, 3252–3257 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Adler, S.H. et al. Notch signaling augments T cell responsiveness by enhancing CD25 expression. J. Immunol. 171, 2896–2903 (2003).

    Article  CAS  PubMed  Google Scholar 

  41. Adams, W.C. et al. Attenuation of CD4+ T-cell function by human adenovirus type 35 is mediated by the knob protein. J. Gen. Virol. 93, 1339–1344 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Adams, W.C. et al. Adenovirus type-35 vectors block human CD4+ T-cell activation via CD46 ligation. Proc. Natl. Acad. Sci. USA 108, 7499–7504 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  43. Gibb, A.L., Freeman, A.M., Smith, R.A., Edmonds, S. & Sim, E. The interaction of soluble human complement receptor type 1 (sCR1, BRL55730) with human complement component C4. Biochim. Biophys. Acta 1180, 313–320 (1993).

    Article  CAS  PubMed  Google Scholar 

  44. Marley, J., Lu, M. & Bracken, C. A method for efficient isotopic labeling of recombinant proteins. J. Biomol. NMR 20, 71–75 (2001).

    Article  CAS  PubMed  Google Scholar 

  45. White, J. et al. Biological activity, membrane-targeting modification, and crystallization of soluble human decay accelerating factor expressed in E. coli. Protein Sci. 13, 2406–2415 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Roversi, P. et al. Structures of the rat complement regulator CrrY. Acta Crystallogr. Sect. F Struct. Biol. Cryst. Commun. 67, 739–743 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. 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 

  48. Schleucher, J. et al. A general enhancement scheme in heteronuclear multidimensional NMR employing pulsed field gradients. J. Biomol. NMR 4, 301–306 (1994).

    Article  CAS  PubMed  Google Scholar 

  49. Yamazaki, T., Lee, W., Arrowsmith, C.H., Muhandiram, D.R. & Kay, L.E. A Suite of triple-resonance NMR experiments for the backbone assignment of N-15, C-13, H-2 labeled proteins with high-sensitivity. J. Am. Chem. Soc. 116, 11655–11666 (1994).

    Article  CAS  Google Scholar 

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Acknowledgements

We thank the CD46-deficient patients and patients with Alagille syndrome for their support, and A. Hayday for data discussions. Supported by the Medical Research Council (G1002165 to C.K.), the European Union Framework Programme 7 (Innovative Medicines Initiative “Be The Cure” project with C.K. as lead researcher), the Medical Research Council Centre for Transplantation (Guy's Hospital, King's College), the Department of Health, the National Institute for Health Research Biomedical Research Centre (for Guy's & St. Thomas' National Health Service Foundation Trust in partnership with King's College London and King's College Hospital National Health Service Foundation Trust), the Wellcome Trust (097928/A/08/Z to S.M.L. and P.A.H.), the German Research Foundation (GRK1727 TP8 and SFB/TR22 A21 to J.K.) and the European Research Council ('SomaBio' to S.N.W.).

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Author notes

  1. Pat Whiteman, Christian M Karsten and Salley Al-Tilib Shamoun: These authors contributed equally to this work.

Authors and Affiliations

  1. Division of Transplantation Immunology and Mucosal Biology, MRC Centre for Transplantation, King's College London, Guy's Hospital, London, UK

    Gaëlle Le Friec, Adam Laing, Teresa Melchionna, Richard A Smith & Claudia Kemper

  2. Sir William Dunn School of Pathology, University of Oxford, Oxford, UK

    Devon Sheppard & Susan M Lea

  3. Department of Biochemistry, University of Oxford, Oxford, UK

    Pat Whiteman, Chandramouli Chillakuri & Penny A Handford

  4. Institute for Systemic Inflammation Research, University of Lübeck, Lübeck, Germany

    Christian M Karsten & Jörg Köhl

  5. Child Health Clinical Academic Grouping, King's Health Partners, Denmark Hill Campus, London, UK

    Salley Al-Tilib Shamoun & Alastair Baker

  6. Division of Cell and Molecular Biology, Department of Life Sciences, Imperial College London, London, UK

    Laurence Bugeon & Margaret J Dallman

  7. Université Joseph Fourier, Groupe de Recherche et d'Etude du Processus Inflammatoire–Age and Imaging Research Unit, Centre National de la Recherche Scientifique FRE3405, CHU de Grenoble, Grenoble, France

    Christian Drouet

  8. Nephrology-Transplantation, CHU Bordeaux, Bordeaux, France

    Lionel Couzi

  9. Cordeliers Research Center, Inserm Unite Mixte de Recherche en Sante 872, Paris, France

    Veronique Fremeaux-Bacchi

  10. Hopital Europeen Georges Pompidou, Service d'Immunologie Biologique, Assistance Publique–Hopitaux de Paris, Paris, France

    Veronique Fremeaux-Bacchi

  11. Division of Cellular and Molecular Immunology, Cincinnati Children's Hospital Medical Center and University of Cincinnati College of Medicine, Cincinnati, Ohio, USA

    Jörg Köhl

  12. Institute for Women's Health, Gene Transfer Technology Group, University College London, London, UK

    Simon N Waddington

  13. Randall Division of Cell & Molecular Biophysics, King's College London, UK

    James M McDonnell

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  1. Gaëlle Le Friec
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Contributions

A.B. and P.A.H. contributed equally to this work. G.L.F. designed and did experiments and wrote the manuscript; D.S. did surface plasmon resonance and nuclear magnetic resonance spectroscopy experiments; P.W. and C.C. generated recombinant Notch and Jagged1 proteins; C.M.K. and J.K. did the super-resolution microscope studies and edited the manuscript; S.A.-T.S., A.B., C.D., L.C. and V.F.-B. provided blood samples from patients and discussed the data; A.L. did the graft-versus-host disease experiments and discussed data; L.B. and M.J.D. designed the RT-PCR experiments and discussed the data; T.M. and R.A.S. generated soluble CD46 and soluble complement receptor 1 and discussed data; S.N.W. provided mice with transgenic expression of human CD46 and edited the paper; J.M.M. did surface plasmon resonance experiments and edited the paper; P.A.H. provided recombinant Notch and Jagged proteins, designed experiments and edited the paper; S.M.L. designed the surface plasmon resonance and nuclear magnetic resonance experiments, provided recombinant CD46 proteins and edited the manuscript; and C.K. conceived of and designed the study, did experiments and edited the manuscript.

Corresponding author

Correspondence to Claudia Kemper.

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Le Friec, G., Sheppard, D., Whiteman, P. et al. The CD46-Jagged1 interaction is critical for human TH1 immunity. Nat Immunol 13, 1213–1221 (2012). https://doi.org/10.1038/ni.2454

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