Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Role of IL-27 in Epstein–Barr virus infection revealed by IL-27RA deficiency

Nature volume 628, pages 620–629 (2024)Cite this article

Subjects

Abstract

Epstein–Barr virus (EBV) infection can engender severe B cell lymphoproliferative diseases1,2. The primary infection is often asymptomatic or causes infectious mononucleosis (IM), a self-limiting lymphoproliferative disorder3. Selective vulnerability to EBV has been reported in association with inherited mutations impairing T cell immunity to EBV4. Here we report biallelic loss-of-function variants in IL27RA that underlie an acute and severe primary EBV infection with a nevertheless favourable outcome requiring a minimal treatment. One mutant allele (rs201107107) was enriched in the Finnish population (minor allele frequency = 0.0068) and carried a high risk of severe infectious mononucleosis when homozygous. IL27RA encodes the IL-27 receptor alpha subunit5,6. In the absence of IL-27RA, phosphorylation of STAT1 and STAT3 by IL-27 is abolished in T cells. In in vitro studies, IL-27 exerts a synergistic effect on T-cell-receptor-dependent T cell proliferation7 that is deficient in cells from the patients, leading to impaired expansion of potent anti-EBV effector cytotoxic CD8+ T cells. IL-27 is produced by EBV-infected B lymphocytes and an IL-27RA–IL-27 autocrine loop is required for the maintenance of EBV-transformed B cells. This potentially explains the eventual favourable outcome of the EBV-induced viral disease in patients with IL-27RA deficiency. Furthermore, we identified neutralizing anti-IL-27 autoantibodies in most individuals who developed sporadic infectious mononucleosis and chronic EBV infection. These results demonstrate the critical role of IL-27RA–IL-27 in immunity to EBV, but also the hijacking of this defence by EBV to promote the expansion of infected transformed B cells.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Identification of IL-27RA deficiency in patients with severe EBV primo infection.
Fig. 2: Defective STAT1 and STAT3 phosphorylation and proliferation of IL-27RA-deficient T cells in response to IL-27 is rescued by wild-type IL-27RA expression.
Fig. 3: Impaired expansion and differentiation of EBV-specific IL-27RA-deficient CD8+ T cells towards EBV-infected B cells.
Fig. 4: IL-27RA–IL-27 is essential for the maintenance of EBV-transformed B cells.
Fig. 5: The presence of neutralizing anti-IL-27 autoantibodies in the serum of patients with IM.

Similar content being viewed by others

Data availability

All data supporting the findings of this study are available within the Article and its Supplementary Information. Source data are available at Figshare (https://doi.org/10.6084/m9.figshare.25062611). Original data are available from the corresponding author and E.M. (emmanuel.martin@inserm.fr) on reasonable request. Exome-sequencing data of patients are not publicly available due to ethical restrictions, including the possibility of revealing identifying information, to which the patients have not consented. Source data are provided with this paper.

References

  1. Latour, S. & Fischer, A. Signaling pathways involved in the T-cell-mediated immunity against Epstein-Barr virus: lessons from genetic diseases. Immunol. Rev. 291, 174–189 (2019).

    Article  CAS  PubMed  Google Scholar 

  2. Taylor, G. S., Long, H. M., Brooks, J. M., Rickinson, A. B. & Hislop, A. D. The immunology of Epstein-Barr virus-induced disease. Annu. Rev. Immunol. 33, 787–821 (2015).

    Article  CAS  PubMed  Google Scholar 

  3. Dunmire, S. K., Hogquist, K. A. & Balfour, H. H. Infectious mononucleosis. Curr. Top. Microbiol. Immunol. 390, 211–240 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Tangye, S. G. & Latour, S. Primary immunodeficiencies reveal the molecular requirements for effective host defense against EBV infection. Blood 135, 644–655 (2020).

    Article  PubMed  Google Scholar 

  5. Hirahara, K. et al. Asymmetric action of STAT transcription factors drives transcriptional outputs and cytokine specificity. Immunity 42, 877–889 (2015).

    Article  CAS  PubMed  Google Scholar 

  6. Kastelein, R. A., Hunter, C. A. & Cua, D. J. Discovery and biology of IL-23 and IL-27: related but functionally distinct regulators of inflammation. Annu. Rev. Immunol. 25, 221–242 (2007).

    Article  CAS  PubMed  Google Scholar 

  7. Huang, Z. et al. IL-27 promotes the expansion of self-renewing CD8+ T cells in persistent viral infection. J. Exp. Med. 216, 1791–1808 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Munz, C. Latency and lytic replication in Epstein-Barr virus-associated oncogenesis. Nat. Rev. Microbiol. 17, 691–700 (2019).

    Article  CAS  PubMed  Google Scholar 

  9. Shannon-Lowe, C. & Rickinson, A. The global landscape of EBV-associated tumors. Front. Oncol. 9, 713 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  10. Callan, M. F. et al. Direct visualization of antigen-specific CD8+ T cells during the primary immune response to Epstein-Barr virus In vivo. J. Exp. Med. 187, 1395–1402 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Karczewski, K. J. et al. The mutational constraint spectrum quantified from variation in 141,456 humans. Nature 581, 434–443 (2020).

    Article  CAS  PubMed  PubMed Central  ADS  Google Scholar 

  12. Sprecher, C. A. et al. Cloning and characterization of a novel class I cytokine receptor. Biochem. Biophys. Res. Commun. 246, 82–90 (1998).

    Article  CAS  PubMed  Google Scholar 

  13. Pflanz, S. et al. WSX-1 and glycoprotein 130 constitute a signal-transducing receptor for IL-27. J. Immunol. 172, 2225–2231 (2004).

    Article  CAS  PubMed  Google Scholar 

  14. Chen, Q. et al. Development of Th1-type immune responses requires the type I cytokine receptor TCCR. Nature 407, 916–920 (2000).

    Article  CAS  PubMed  ADS  Google Scholar 

  15. Owaki, T. et al. A role for IL-27 in early regulation of Th1 differentiation. J. Immunol. 175, 2191–2200 (2005).

    Article  CAS  PubMed  Google Scholar 

  16. Yoshida, H. & Hunter, C. A. The immunobiology of interleukin-27. Annu. Rev. Immunol. 33, 417–443 (2015).

    Article  CAS  PubMed  Google Scholar 

  17. Artis, D. et al. The IL-27 receptor (WSX-1) is an inhibitor of innate and adaptive elements of type 2 immunity. J. Immunol. 173, 5626–5634 (2004).

    Article  CAS  PubMed  Google Scholar 

  18. Schneider, R., Yaneva, T., Beauseigle, D., El-Khoury, L. & Arbour, N. IL-27 increases the proliferation and effector functions of human naive CD8+ T lymphocytes and promotes their development into Tc1 cells. Eur. J. Immunol. 41, 47–59 (2011).

    Article  CAS  PubMed  Google Scholar 

  19. Charlot-Rabiega, P., Bardel, E., Dietrich, C., Kastelein, R. & Devergne, O. Signaling events involved in interleukin 27 (IL-27)-induced proliferation of human naive CD4+ T cells and B cells. J. Biol. Chem. 286, 27350–27362 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Pflanz, S. et al. IL-27, a heterodimeric cytokine composed of EBI3 and p28 protein, induces proliferation of naive CD4+ T cells. Immunity 16, 779–790 (2002).

    Article  CAS  PubMed  Google Scholar 

  21. Pagano, G. et al. Interleukin-27 potentiates CD8+ T-cell-mediated anti-tumor immunity in chronic lymphocytic leukemia. Haematologica https://doi.org/10.3324/haematol.2022.282474 (2023).

  22. Harker, J. A. et al. Interleukin-27R signaling mediates early viral containment and impacts innate and adaptive immunity after chronic lymphocytic choriomeningitis virus infection. J. Virol. https://doi.org/10.1128/JVI.02196-17 (2018).

  23. Pratumchai, I. et al. B cell-derived IL-27 promotes control of persistent LCMV infection. Proc. Natl Acad. Sci. USA https://doi.org/10.1073/pnas.2116741119 (2022).

  24. Devergne, O., Birkenbach, M. & Kieff, E. Epstein-Barr virus-induced gene 3 and the p35 subunit of interleukin 12 form a novel heterodimeric hematopoietin. Proc. Natl Acad. Sci. USA 94, 12041–12046 (1997).

    Article  CAS  PubMed  PubMed Central  ADS  Google Scholar 

  25. Devergne, O. et al. A novel interleukin-12 p40-related protein induced by latent Epstein-Barr virus infection in B lymphocytes. J. Virol. 70, 1143–1153 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Niedobitek, G., Pazolt, D., Teichmann, M. & Devergne, O. Frequent expression of the Epstein-Barr virus (EBV)-induced gene, EBI3, an IL-12 p40-related cytokine, in Hodgkin and Reed-Sternberg cells. J. Pathol. 198, 310–316 (2002).

    Article  CAS  PubMed  Google Scholar 

  27. Larousserie, F. et al. Analysis of interleukin-27 (EBI3/p28) expression in Epstein-Barr virus- and human T-cell leukemia virus type 1-associated lymphomas: heterogeneous expression of EBI3 subunit by tumoral cells. Am. J. Pathol. 166, 1217–1228 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Kang, M. S. & Kieff, E. Epstein-Barr virus latent genes. Exp. Mol. Med. 47, e131 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Tosato, G. et al. Monocyte-derived human B-cell growth factor identified as interferon-β2 (BSF-2, IL-6). Science 239, 502–504 (1988).

    CAS  PubMed  ADS  Google Scholar 

  30. Tosato, G., Tanner, J., Jones, K. D., Revel, M. & Pike, S. E. Identification of interleukin-6 as an autocrine growth factor for Epstein-Barr virus-immortalized B cells. J. Virol. 64, 3033–3041 (1990).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Chehboun, S. et al. Epstein-Barr virus-induced gene 3 (EBI3) can mediate IL-6 trans-signaling. J. Biol. Chem. 292, 6644–6656 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Puel, A., Bastard, P., Bustamante, J. & Casanova, J. L. Human autoantibodies underlying infectious diseases. J. Exp. Med. https://doi.org/10.1084/jem.20211387 (2022).

  33. Kisand, K. et al. Chronic mucocutaneous candidiasis in APECED or thymoma patients correlates with autoimmunity to Th17-associated cytokines. J. Exp. Med. 207, 299–308 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Puel, A. et al. Autoantibodies against IL-17A, IL-17F, and IL-22 in patients with chronic mucocutaneous candidiasis and autoimmune polyendocrine syndrome type I. J. Exp. Med. 207, 291–297 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Nanki, T. et al. Suppression of elevations in serum C reactive protein levels by anti-IL-6 autoantibodies in two patients with severe bacterial infections. Ann. Rheum. Dis. 72, 1100–1102 (2013).

    Article  CAS  PubMed  Google Scholar 

  36. Puel, A. et al. Recurrent staphylococcal cellulitis and subcutaneous abscesses in a child with autoantibodies against IL-6. J. Immunol. 180, 647–654 (2008).

    Article  CAS  PubMed  Google Scholar 

  37. Bastard, P. et al. Autoantibodies against type I IFNs in patients with life-threatening COVID-19. Science https://doi.org/10.1126/science.abd4585 (2020).

  38. Bastard, P. et al. Auto-antibodies to type I IFNs can underlie adverse reactions to yellow fever live attenuated vaccine. J. Exp. Med. https://doi.org/10.1084/jem.20202486 (2021).

  39. Zhang, Q. et al. Autoantibodies against type I IFNs in patients with critical influenza pneumonia. J. Exp. Med. https://doi.org/10.1084/jem.20220514 (2022).

  40. Fournier, B. & Latour, S. Immunity to EBV as revealed by immunedeficiencies. Curr. Opin. Immunol. 72, 107–115 (2021).

    Article  CAS  PubMed  Google Scholar 

  41. Kawamoto, K. et al. A distinct subtype of Epstein-Barr virus-positive T/NK-cell lymphoproliferative disorder: adult patients with chronic active Epstein-Barr virus infection-like features. Haematologica 103, 1018–1028 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Alosaimi, M. F. et al. Immunodeficiency and EBV-induced lymphoproliferation caused by 4-1BB deficiency. J. Allergy Clin. Immunol. 144, 574–583 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Rodriguez, R. et al. Concomitant PIK3CD and TNFRSF9 deficiencies cause chronic active Epstein-Barr virus infection of T cells. J. Exp. Med. 216, 2800–2818 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Somekh, I. et al. CD137 deficiency causes immune dysregulation with predisposition to lymphomagenesis. Blood 134, 1510–1516 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Hoshino, Y., Nishikawa, K., Ito, Y., Kuzushima, K. & Kimura, H. Kinetics of Epstein-Barr virus load and virus-specific CD8+ T cells in acute infectious mononucleosis. J. Clin. Virol. 50, 244–246 (2011).

    Article  CAS  PubMed  Google Scholar 

  46. Martin, E. et al. CTP synthase 1 deficiency in humans reveals its central role in lymphocyte proliferation. Nature 510, 288–292 (2014).

    Article  CAS  PubMed  PubMed Central  ADS  Google Scholar 

  47. Yamazaki, Y. et al. Two novel gain-of-function mutations of STAT1 responsible for chronic mucocutaneous candidiasis disease: impaired production of IL-17A and IL-22, and the presence of anti-IL-17F autoantibody. J. Immunol. 193, 4880–4887 (2014).

    Article  CAS  PubMed  Google Scholar 

  48. Toubiana, J. et al. Heterozygous STAT1 gain-of-function mutations underlie an unexpectedly broad clinical phenotype. Blood 127, 3154–3164 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Izawa, K. et al. Inherited CD70 deficiency in humans reveals a critical role for the CD70-CD27 pathway in immunity to Epstein-Barr virus infection. J. Exp. Med. 214, 73–89 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Durandy, A., Kracker, S. & Fischer, A. Primary antibody deficiencies. Nat. Rev. Immunol. 13, 519–533 (2013).

    Article  CAS  PubMed  Google Scholar 

  51. Fournier, B. et al. Rapid identification and characterization of infected cells in blood during chronic active Epstein-Barr virus infection. J. Exp. Med. https://doi.org/10.1084/jem.20192262 (2020).

  52. McStay, G. P., Salvesen, G. S. & Green, D. R. Overlapping cleavage motif selectivity of caspases: implications for analysis of apoptotic pathways. Cell Death Differ. 15, 322–331 (2008).

    Article  CAS  PubMed  Google Scholar 

  53. Dobin, A. et al. STAR: ultrafast universal RNA-seq aligner. Bioinformatics 29, 15–21 (2013).

    Article  CAS  PubMed  Google Scholar 

  54. Anders, S., Pyl, P. T. & Huber, W. HTSeq—a Python framework to work with high-throughput sequencing data. Bioinformatics 31, 166–169 (2015).

    Article  CAS  PubMed  Google Scholar 

  55. Love, M. I., Huber, W. & Anders, S. Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol. 15, 550 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  56. Edgar, R., Domrachev, M. & Lash, A. E. Gene Expression Omnibus: NCBI gene expression and hybridization array data repository. Nucleic Acids Res. 30, 207–210 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank the patients and the families for their contribution and the healthy donors for blood gifts; M. Zarhrate, C. Bole and N. Cagnard for technical assistance; and the staff at the Service de Biochimie Générale, Hospital Necker-Enfants Malades for testing EBV antibodies in sera. S.L. is a senior scientist at the Centre National de la Recherche Scientifique-CNRS (France). C.G. is supported by the Agence Nationale de Recherche (ANR, France). This work was supported by grants from the Ligue Contre le Cancer-Equipe Labélisée (to S.L.), the Institut National de la Santé et de la Recherche Médicale, the Agence Nationale de Recherche (ANR-18-CE15-0025-01 to S.L., ANR-10-IAHU-01 to Institut Imagine and ANR-21-CE15-0018 to E.M.), the Institut National du Cancer (PLBIO-2020_LATOUR, PEDIAC consortium INCa_15670, PEDIAHR22_017), the Société Française de Lutte contre les Cancers et Leucémies de l’Enfant et de l’Adolescent, AREMIG (to S.L.) and the Fédération Enfants et Santé (to S.L.). Exome sequencing was funded by the Rare Diseases Foundation (to S.L.). C.S.M. and S.G.T. are supported by Investigator grants awarded by the National Health and Medical Research Council of Australia.

Author information

Author notes

  1. These authors contributed equally: Cécile Garcin, Kay Tanita, Akihiro Hoshino, Christelle Lenoir

  2. These authors jointly supervised this work: Bénédicte Neven, Alain Fischer

Authors and Affiliations

  1. Laboratory of Lymphocyte Activation and Susceptibility to EBV infection, INSERM UMR 1163, Imagine Institute, Paris, France

    Emmanuel Martin, Sarah Winter, Cécile Garcin, Kay Tanita, Akihiro Hoshino, Christelle Lenoir, Benjamin Fournier, Mathieu Simonin, Anne-Laure Roupie, Yassine Ben Ahmed, Claire Soudais, Capucine Picard & Sylvain Latour

  2. Université Paris Cité, Paris, France

    Sarah Winter, Cécile Garcin, David Boutboul, Paul Bastard, Tom Le Voyer, Anne-Laure Roupie, Claire Soudais, Capucine Picard, Jacinta Bustamante, Anne Puel, Jean-Laurent Casanova & Sylvain Latour

  3. Department of Pediatric Immunology, Hematology and Rheumatology, Necker-Enfants Malades Hospital, Assistance Publique–Hôpitaux de Paris (APHP), Paris, France

    Benjamin Fournier, Jean-Laurent Casanova, Bénédicte Neven & Alain Fischer

  4. Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR 1163, Imagine Institute, Paris, France

    Mélanie Migaud, Paul Bastard, Tom Le Voyer, Jacinta Bustamante, Anne Puel & Jean-Laurent Casanova

  5. Department of Hematology, Cochin Hospital, AP-HP, Paris, France

    David Boutboul

  6. Plateforme Vecteurs Viraux et Transfert de Gènes, Institut Necker Enfants Malades, Necker-Enfants Malades Hospital, APHP, Paris, France

    Alicia Fernandes

  7. Service de Bactériologie, Virologie, Parasitologie et Hygiène, Necker-Enfants Malades Hospital, Paris, France

    Marianne Leruez-Ville & Marianne Burgard

  8. Garvan Institute of Medical Research, Darlinghurst, Sydney, New South Wales, Australia

    Geetha Rao, Cindy S. Ma & Stuart G. Tangye

  9. St Vincent’s Clinical School, Faculty of Medicine and Health, Sydney, New South Wales, Australia

    Cindy S. Ma & Stuart G. Tangye

  10. Plateforme de Bioinformatique, INSERM UMR1163, Université de Paris, Imagine Institute, Paris, France

    Cécile Masson

  11. Study Center for Primary Immunodeficiencies, Necker-Enfants Malades Hospital, APHP, Paris, France

    Capucine Picard & Jacinta Bustamante

  12. St Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, USA

    Jacinta Bustamante, Anne Puel & Jean-Laurent Casanova

  13. Hôpital Jean Minjoz, Centre Hospitalo-Universitaire de Besançon, Besançon, France

    Nathalie Cheikh

  14. Pediatric Research Center and Rare Disease Center, New Children’s Hospital, University of Helsinki and HUS Helsinki University Hospital, Helsinki, Finland

    Mikko Seppänen

  15. Institut for Molecular Medecine Finland, University of Helsinki, Helsinki, Finland

    Mark Daly

  16. Howard Hughes Medical Institute, New York, NY, USA

    Jean-Laurent Casanova

  17. Collège de France, Paris, France

    Alain Fischer

  18. Imagine Institute, INSERM UMR 1163, Paris, France

    Alain Fischer

Authors
  1. Emmanuel Martin
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sarah Winter
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Cécile Garcin
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Kay Tanita
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Akihiro Hoshino
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Christelle Lenoir
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Benjamin Fournier
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Mélanie Migaud
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. David Boutboul
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Mathieu Simonin
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Alicia Fernandes
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Paul Bastard
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Tom Le Voyer
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Anne-Laure Roupie
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Yassine Ben Ahmed
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Marianne Leruez-Ville
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Marianne Burgard
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Geetha Rao
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. Cindy S. Ma
    View author publications

    You can also search for this author in PubMed Google Scholar

  20. Cécile Masson
    View author publications

    You can also search for this author in PubMed Google Scholar

  21. Claire Soudais
    View author publications

    You can also search for this author in PubMed Google Scholar

  22. Capucine Picard
    View author publications

    You can also search for this author in PubMed Google Scholar

  23. Jacinta Bustamante
    View author publications

    You can also search for this author in PubMed Google Scholar

  24. Stuart G. Tangye
    View author publications

    You can also search for this author in PubMed Google Scholar

  25. Nathalie Cheikh
    View author publications

    You can also search for this author in PubMed Google Scholar

  26. Mikko Seppänen
    View author publications

    You can also search for this author in PubMed Google Scholar

  27. Anne Puel
    View author publications

    You can also search for this author in PubMed Google Scholar

  28. Mark Daly
    View author publications

    You can also search for this author in PubMed Google Scholar

  29. Jean-Laurent Casanova
    View author publications

    You can also search for this author in PubMed Google Scholar

  30. Bénédicte Neven
    View author publications

    You can also search for this author in PubMed Google Scholar

  31. Alain Fischer
    View author publications

    You can also search for this author in PubMed Google Scholar

  32. Sylvain Latour
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

E.M. and S.W. designed, performed experiments and analysed data. E.M. participated in the writing of the manuscript. A. Fernandes, C.G., C.L., A.-L.R., Y.B.A., A.H., C.S.M., G.R., K.T. and S.G.T. performed experiments and analysed the data. M.D. and M.S. provided and analysed data from FinnGen. M. Simonin, T.L.V., P.B., M.-L.V., M.B., B.F., C.M., M.M., D.B., J.B., C.S., A.P. and J.-L.C. provided samples and/or reagents and/or analysed data. B.F., N.C. and B.N. identified the patients provided and analysed clinical data. A.F. analysed data and participated in the writing of the manuscript. S.L. wrote the manuscript, designed and supervised the research.

Corresponding author

Correspondence to Sylvain Latour.

Ethics declarations

Competing interests

The authors declare no competing interests.

Peer review

Peer review information

Nature thanks the anonymous reviewers for their contribution to the peer review of this work.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Extended data figures and tables

Extended Data Fig. 1 Immunophenotyping of IL-27RA-deficient patients.

a, Frequencies of the different lymphocyte populations from PBMCs of patients (P1.1, P1.2 and P2) and controls represented by graph bars from data obtained From FACS analysis after cell-specific staining. T, B and NK subpopulations are shown in upper panels. αβ, γδ, CD4, CD8 T cells and innate-like T cells (MAIT and iNKT) gated in CD3+ or Treg gated in CD4 + T cells are shown in middle panels. Naïve (CD31+CD45RA+CCR7+), central memory (CD45RA−CCR7+CD27+), effector memory (CD45RA−CCR7−CD27−) and exhausted effector memory/TEMRA (CD45RA+CCR7−CD27−) compartments in CD4+ and CD8+ T cells are shown in lower panels. b, Representative dot plots from FACS analysis of follicular helper T cell (Tfh) population (left panel). Graph bars (right panel) representing the frequencies in percent of Tfh cells (CD4+CD45RA− CD127 + CD25- CXCR5 +) gated on CD3+ cells. Data obtained from FACS analysis as shown in the left dot plots. c, Representative dot plot FACS analysis of non-follicular (CXCR5−) T helper cell subpopulations, Th1 (CCR4−CXCR3+CCR6−), Th1* (CCR4−CXCR3+CCR6+) Th2 (CCR4+CXCR3−CCR6−) and Th17 (CCR4+CXCR3+−CCR6+) populations (left panel). Graph bars (right panel) representing the frequencies in percent of Th1/1*/2/17 cells gated on memory CD4+ T cells (no Tfh). Data obtained from FACS analysis of dot plots as shown in the left panel. (a,b,c) Data are medians ± s.d. with each symbol/circle represents an independent biological/experimental sample. Ten to 15 age-matched controls and 3 patients were analysed. The horizontal bars represent the median±sd. Data obtained from six independent experiments. Two-tailed Mann-Whitney tests were used. d, Graph bars corresponding to medians ± s.d. of IL-2, IL-22, IFN-γ and TNF-α cytokines levels from coated bead array (CBA) quantifications in culture of naïve and memory sorted CD4 T cells of grouped P1.1 and P1.2 IL27RA-deficient patients (red, n = 5) compared to controls (grey, n = 5) stimulated with CD3/28/2 beads (Th0), CD3/28/2 beads and IL-12 (Th1) or CD3/28/2 beads and IL-27 (IL-27) during 5 days. Data were obtained from FACS analysis. Each symbol/circle represents an independent biological/experimental sample. Two-tailed Wilcoxon-Mann-Whitney tests were used.

Source Data

Extended Data Fig. 2 Effect of the c.1142-2A>C and c.1336C>G mutations in IL27RA gene of family 2.

a, 45 nucleotide in-frame deletion resulting from the heterozygous c.1142-2A>C mutation in P2. On the left, PCR products from the amplification of cDNAs obtained from activated P2 and two control T cell blasts with forward and reverse oligonucleotides are depicted on a diagram corresponding to IL27RA cDNA from exons 7 to 11 (right panel). The size and structures of the potential PCR products are listed. The wild-type and the 45 nucleotide deleted products are indicated by black arrows on the right side of the gel. The lower panel shows the electropherogram of SANGER sequencing of the 515 bp product focused on the region containing the 45 nucleotide deletion. The sequence is depicted on the top with the deleted sequence (45 bp) in red and the new acceptor splice site in red bold. Data from one experiment. b, Same as in (a) excepted that PCR products from amplification of cDNAs were obtained from two control LCLs (Ctrl.1, Ctrl.2) or LCLs of P1.1, P1.2 and P2. Data from one experiment. c-d, Analyses of IL27RA expression in control T-cell blasts and T-cell blasts from P2 and her parents. c, pictures showing representative immunofluorescent stainings of surface IL27RA (green) and intracellular+ surface IL-27RA (red) expression. Staining of the nucleus was performed using DAPI labelling (blue). Scales 4 μM. d, Histograms from flow cytometry analysis. Data from one representative experiment of two.

Extended Data Fig. 3 Defective IL-27-induced STAT1 and STAT3 phosphorylation and proliferation of T-cells in Patient P2.

a, Immunoblots for phospho-STAT1 (P-STAT1), STAT1, phospho-STAT3 (P-STAT3), STAT3 and ACTIN expression in T-cell blasts of control 1 (Ctrl.1), control 2 (Ctrl.2) or IL27RA-deficient patient P2 (P2) stimulated with 50 ng.ml−1 of human recombinant IL-27 for different periods of time. Data from one representative experiment of two. b, Histograms from FACS analysis showing intracellular phospho-STAT1, phospho-STAT3 expression and corresponding isotypes (clear) in controls (grey) or P2 (red) T-cell blasts stimulated (dark) or not (light) with IL-27 cytokine during 15 min. Data from one representative experiment of two. c, Residual STAT1 and STAT3 phosphorylations of control and IL27RA deficient T-cell blasts when cultured in the presence of IL-2. Immunoblots for phospho-STAT1, STAT1, phospho-STAT3, STAT3, and GAPDH expressions in non-stimulated T-cell blasts of control healthy donors (Ctrl.1 and Ctrl.2) and IL27RA-deficient patients (P1.1 and P1.2) maintained in culture with IL-2 or washed 3 times and then starved during 2 days (IL-2 starvation). Data from one representative experiment of two. d, Overlaid FACS histograms showing cell divisions by dilution of Cell Trace Violet (CTV) dye of T cells from a healthy control (Ctrl.) (grey), parents of P2 (grey) and IL27RA-deficient patient P2 (red) stimulated with allow concentration of coated anti-CD3 antibody (0.1 µg.ml−1) in presence (dark) or not (light) of 50 ng.ml−1 of IL-27 during five days. Data from one representative experiment of two. e-g, IL-27 promotes the proliferation of naive T cells. T cells from control PBMCs stimulated with anti-CD3 antibody (0.1μg.ml−1) in presence or not of IL-27 (50 ng.ml−1) during five days. e, Overlaid FACS histograms showing cell divisions by dilution of cell trace violet (CTV) dye of T cells that have been incubated or not with anti-IL-27 blocking antibody. One representative experiment of four. f, Overlaid FACS histograms on left panels showing cell divisions by dilution of cell trace violet (CTV) dye of naïve CD45RA+CD27+ (upper panels) and memory CD45RA- CD27 + T cells (lower panels). Data from one representative experiment of three. g, Graphs corresponding to replication index calculated from FACS histograms as in (f) of three independent experiments in which PBMCs of healthy donors (n = 4) have been tested. Stimulations with anti-CD3 alone or with anti-CD3 plus IL-27 correspond to white or black circles respectively. Black line represents the medians and each symbol/circle represents an independent biological/experimental sample. Two-tailed paired t-tests were used.

Source Data

Extended Data Fig. 4 The IL27RA R466G mutant is weakly expressed and is able to activate STAT1 and STAT3.

NIH-3T3 cells have been transfected with lentiviral expression vectors containing a cDNA coding wild type IL27RA (black), IL27RA Arg446Gly (red), IL27RA G381_A395del mutant (orange) or an empty vector (white) with the mCherry as a reporter gene of transfected cells. a, Overlaid histograms from FACS analysis showing IL-27RA expression in mCherry+ cells. Dashed line histograms for isotype control. One representative experiment of 3 independent experiments. b, Histograms from FACS analyses in the left depicting intracellular phospho-STAT1 (P-STAT1) expression in cells stimulated with human IL-27 or not (No. stim.). The bar graphs on the right correspond to P-STAT1 mean fluorescence intensities (MFI) normalized on the corresponding isotype MFI. MFI were calculated from histograms as shown on the left. c, same as b, except that phospho-STAT3 (P-STAT3) expression was analysed. (b-c). Errors bars represent the median ± s.d. The symbols correspond to three experimental replicates from two independent experiments (triangles and circles). Two-tailed paired t tests were used.

Source Data

Extended Data Fig. 5 Impaired differentiation of IL27RA-deficient CD8 + T cells toward EBV-infected B cells (LCLs) and normal expression of SAP in PBMCs of P1.1.

a, Graph bars corresponding to medians ± s.d. of percentages of healthy donors (black, n = 7), P1.1 (dark red, n = 5) or P1.2 (light red, n = 1) EBV-pentamers negative CD8+ T expressing activation, differentiation and exhaustion T-cell markers from PBMCs co-cultured with LCLs at day 0 (upper graph) and day 9 (lower graph). Yellow squares correspond to P1.1 at the time she had severe infectious mononucleosis (P1.1-SIM). Data were obtained from FACS analysis of seven independent experiments. Each symbol represents an independent biological sample. Two-tailed paired t-tests were used. b, Graph bars corresponding to the median ± s.d. of percentages of EBV-specific T cells from P2 (red, n = 1) and controls (Ctrl.) (black, n = 4) expressing activation, differentiation and exhaustion T-cell markers and gated on CD8+ T cells at day 0 or day 9 of co-culture with autologous EBV-infected B cells (LCLs). Each symbol/circle represents one independent biological/experimental sample. c, Intracellular staining for SAP in PBMCs of one control (Ctrl.) and patient P1.1. Gating on B cells, NK cells and T cells. Empty and filled histograms correspond to staining with control-matched isotype or anti-SAP antibody respectively. One representative experiment of two. d-g, Blockage of the IL-27-IL27RA pathway is associated with an impaired expansion of EBV-specific T cells towards LCLs. FACS analyses of expansion, apoptosis, proliferation and phenotypes of EBV-specific CD8+ T cells from PBMCs of a healthy control co-cultured during 15 days with autologous LCLs in the presence (red) or not (black) of neutralizing anti-IL-27 antibody and recombinant IL-27RA protein. One representative experiment of two. d, Dot plots showing percentages of EBV-specific T cells. e, Overlaid histograms showing activation, differentiation and exhaustion markers in EBV-specific T cells. f, Dot plots showing early (annexin V+, 7-AAD−) and late (annexin V+, 7-AAD−) apoptotic cells. g, FACS histograms showed cell divisions by CTV dye dilution of EBV-specific T cells after 5 days of re-stimulation with autologous LCLs.

Source Data

Extended Data Fig. 6 Characterization of IL27RA-deficient and STAT1-deficient LCLs.

a, Overlaid FACS histograms of HLA-A2 expression in LCLs from two controls (dark grey) and IL27RA-deficient patients (P1.1, P1.2 and P2 in red). Isotype staining corresponds to dashed line histograms. Data from one representative experiment of two. b, Overlaid FACS histograms of CD70 and CD137L (4-1BB/TNFSF9) expression in LCLs from three controls (Ctrl. in black), IL27RA-deficient patients (P1.1, P1.2 and P2 in red) and one STAT1-deficient patient (STAT1 LOF in green). Isotype staining corresponds to dashed line histograms. Data from one representative experiment of two. c, Overlaid FACS histograms showing of EBI3 expression (anti-EBI3 antibody, clone A15058A, Biolegend) and IL-27p28 (anti-IL-27p28 antibody, clone B0315A10, Biolegend) subunits of IL-27 in LCLs from six controls (dark grey), the three IL27RA-deficient patients (P1.1, P1.2 and P2 in red) and two STAT1-deficient patient (STAT1 LOF in green) and the monocyte cell line THP-1 (in blue). Isotype staining corresponds to empty histograms. The specificity of anti-EBI3 and p28 have been verified by WB in Extended Data Fig. 11d. Data obtained from three independent experiments. d, Graphs depicting the time necessary to obtain immortalization of B cells corresponding to LCLs from PBMCs of healthy controls (Ctrl., n = 10) and patients (P1.1 (n = 2), P1.2 (n = 1) and P2 (n = 1)) after incubation with EBV. P1.1 was tested two times independently. Data obtained from three independent experiments. e, Graphs depicting the quantification of IL-27 by ELISA in culture supernatants of LCLs in culture. Each symbol corresponds to the tested LCL of different control donors (Ctrl., n = 8), the three patients with IL27RA deficiency (P1.1, P1.2 and P2, n = 3) and patients with STAT1 deficiency (STAT1 LOF, n = 3). Data from three independent experiments. There is no correspondance between controls LCLs (Ctrl.) in d and e. f, Immunoblots for phospho-STAT1 (P-STAT1), STAT1 and ACTIN expressions in LCLs of controls (Ctrl.) and patients (P1.2, P1.2 and P2) directly prepared from the culture without washing that showed decreased basal P-STAT1 in LCLs of patients compared to control LCLs. One representative experiment of three.

Source Data

Extended Data Fig. 7 IL-27 potentiates cell-cytotoxicity of TSST-1 induced T-cell blasts.

a, Representative graph bars from FACS analysis showing the median ± s.d. of CD8+ T cell percentages from healthy control blast donors (Ctrl., n = 3) and patients (P1.1, n = 1 and P1.2, n = 1) (red) expressing activation and exhaustion markers after incubation (chequered) or not (fully filled) with IL-27 for 48 h. Each symbol represents one independent biological sample. These cells were tested for their cytotoxicity activity shown in Fig. 3d. b-c, Analyses of expansion (a), cytotoxicity (b) and phenotyping (c) of TSST-1 induced T-cell blasts from three healthy control donors. b, Cytotoxic response of TSST-1 induced T cell blasts from healthy control donors (n = 3) at day 8 of culture against TSST-1 pulsed LCLs (black) or not (grey) in the presence (chequered) or not (fully filled) of IL-27. Representative graph bars shows the percentages of FRET activated CASP3+ LCLs corresponding to LCLs killing in which caspase 3 has been activated. The target cells (LCLs)/effector cells (T-cell blasts) ratios are indicated on the x-axis. One representative experiment of two with the same statistical significance. c, Representative graph bars from FACS analysis showing the medians ± s.d. of TCR Vβ2 + CD3 + T cell percentages from unstimulated (Unstim., n = 3) and stimulated healthy control donor PBMCs with the superantigen TSST-1 after 8 days in the presence (chequered grey, n = 3) or not (black, n = 3) of IL-27. d, Representative graph bars from FACS analysis showing the percentages of TCR Vb2+ CD8+ T cells expressing activation and exhaustion markers after 8 days of culture in the presence (chequered) or not (fully filled) of IL-27. (a-d). The errors bars represent the median ±s.d. and each symbol/circle corresponds to one biological/experimental sample. (b) two-tailed paired t tests were used.

Source Data

Extended Data Fig. 8 Gene expression by transcriptome analysis including EBV genes of two control LCLs and in two IL27RA-deficient LCLs from two patients P1.1 and P.2.

a, Control LCLs (n = 2; CTL1_basal, CTL2_basal) and IL27RA-deficients LCLs (n = 2; P1.1_basal and P2_basal) display comparable EBV gene expression profiles in basal conditions. The left panel shows boxplots displaying the distribution of gene expression (Log2 normalized) of 10 EBV genes according to IL27RA vs CTL. The boxes in terms of minima, maximun, centre and bounds represent the interquartile range (IQR), demarcating the range between the first and third quartiles. Within this box, a horizontal line denotes the median value of the gene expression. The whiskers extending from the box represent the minimum and maximum values. b, Control (CTL1, CTL2) and IL27RA-deficient (P1.1 and P2) LCLs display different gene expression profiles in response to IL-27 (_stim.) compared to non-stimulated cells (_basal). Left panel, z-score hierarchical heat map visualization of the top 98 genes differentially expressed in each LCL and condition. Gene’s name is on the right. Upper right panel, Gene Ontology analysis (GO; http://geneontology.org/) of the top 200 genes of differentially expressed showing the most significant associated biological pathways. The 15 genes of the « cytokine-mediated signalling pathway » are highlighted. Lower left panel, Volcano plots comparing transcriptome data from control LCLs (left) stimulated with IL-27 versus basal (Stim vs Basal) (left panel) and IL27RA-deficient LCLs (right panel). The 15 genes enriched in the « cytokine-mediated signalling pathway » from the Gene Ontology analysis are indicated.

Extended Data Fig. 9 Defective proliferation and STAT1/3 phosphorylations restored by IL27RA expression in LCLs of patients.

a, Immunoblots for phospho-STAT1 (P-STAT1), STAT1, phospho-STAT3 (P-STAT3), STAT3 and GAPDH expressions in LCLs that were stimulated or not (no stim.) with IL-27 (40 ng.mL−1), IL-2 (10 U.mL−1) or IL-6 (20 ng.mL−1) for 10 min. LCLs from control healthy donors (Ctrl.#1 and Ctrl.#2), IL27RA-deficient patients (P1.2 and P2) and patients with STAT1 loss of function mutations (STAT1 LOF #1 and #2). One representative experiment of two. b, Representative overlaid FACS histograms showing cell divisions by cell trace violet (CTV) dye dilution of healthy control LCLs (Ctrl. 1 and Ctrl.2 in black), LCLs of patients P1.2 and P2 (in red) and LCLs of two patients with STAT1 loss of function (STAT1 LOF#1 and STAT1 LOF#2 in green) at day 0, 3 and 5 of culture. Data were obtained from one of three independent experiments in which additional controls and patients were tested. Calculated expansion indexes are shown in Fig. 4f. c, Histograms from FACS analysis showing IL-27RA expression (upper panel) and corresponding isotype (lower panel) in LCLs of healthy controls (Ctrl.1 and Ctrl.2 in black) and patients (P1.1, P1.2 and P2 in red) transduced with an empty lentivector (Empty pLVX) or a lentivector containing a cDNA coding wild-type IL27RA (pLVX-IL27RA) in filled histograms. Data from one representative experiment of two. d, same as b, except that LCLs from a control and patient P1.2 in which IL27RA expression was restored (pLVX-IL27RA) or not (Empty pLVX) shown in (c) were tested. Data from two independent experiments. Calculated indexes of expansion are shown in Fig. 4g. e, Immunoblots for phospho-STAT1, STAT1 and ACTIN in control LCLs (Ctrl.1, Ctrl.2) and patients LCLs (P1.1, P1.2 and P2) in which IL27RA expression was restored (pLVX-IL27RA) or not (Empty pLVX) shown in (c) that were stimulated or not with IL-27 for 5 min. Data from one of two independent experiments.

Extended Data Fig. 10 IL-27 neutralization or IL27 inactivation in LCLs inhibit proliferation and IL27RA signalling by triggering rapid cell death.

a, Curves of percentages of alive LCLs from three different controls cultured during 14 days in the presence of blocking anti-IL-27 (red, n = 2), anti-IL-2 (grey, n = 1) antibodies or no antibody (black, n = 2). For Ctrl.#1 and #2 curves of two independent experiments for which symbol represent the median ± s.d. of cell percentages. b, Immunoblots for phospho-STAT1, STAT1, phospho-STAT3, STAT3 and ACTIN expressions in LCLs of two controls (Ctrl.1 and Ctrl. 2) stimulated with IL-27 (+) or not (−) in the presence or not of anti-IL-27 or anti-IL-2 blocking antibody at 3 μg.mL−1 for anti-IL-2 (+), 2 μg.mL−1 (+) or 20 μg.mL−1 (++) for anti-IL27. Data from one representative experiment of two. c, Representative FACS density plots (left panels) of DAPI expression of control LCLs in which IL-27 was inactivated or not by transduction with an empty CRISPR-Cas9 vector (left) or CRISPR-Cas9 vector containing gRNAs targeting exon 2 of IL27 (right) and cultured or not (no IL-27) with IL-27 (+ IL-27) for 6 h, left panels. Bar graphs in the right showing percentages of DAPI+ dead control LCLs (grey, n = 3) or LCLs inactivated for IL27 (IL-27 CRISPR in red, n = 3) after 6 h of IL-27 deprivation (dark) or not (light). Each symbol corresponds to one control LCLs. Two independent experiments. Error bars represent median ± s.d., Mann-Whitney two-tailed tests. d, Density plots of intracellular IL-27 expression of control LCLs overexpressing ectopic IL27RA in which IL27 was inactivated by CRISPR-Cas9 targeting the exon 2 of IL27 (IL27 CRISPR), CRISPR-Cas9 empty (Empty CRISPR) vector as negative control. Cells were cultured in the presence of IL-27. Numbers correspond to % of cells in the gates. e, Representative FACS density plots of annexin V and 7-AAD expression of control LCLs transduced with pLVX-IL27RA, in which IL-27 was inactivated (IL27 CRISPR exon2) or not (Empty CRISPR) by CRISPR-Cas9 containing vectors and cultured with IL-27 (+ IL-27) or not (no IL-27) for 8, 24 and 48 h. 7-ADD-Annexin V+ and 7-ADD+Annexin V+ correspond to early and late apoptotic cells respectively. Percentages of cells in each gate. Data from one representative experiment of two.

Source Data

Extended Data Fig. 11 Characterization of anti-IL-27 autoAbs detected in sera of patients with IM.

a, The upper left panel depicts principles of the ELISA to detect anti-IL-27 autoAbs (up) and complexed anti-IL-27 autoAbs with IL-27 (down). Dot plots of levels of anti-IL-27 autoAbs versus IL-27 (upper right panel), IL-27 versus complexed anti-IL-27 autoAbs (lower left panel) and anti-IL-27 autoAbs versus complexed anti-IL-27 autoAbs (lower right panel) in sera of patients with IM (red points) and controls (black points) with regression lines showing significant correlations. b, Detection and quantification of anti-IL-27 IgG and IgA antibodies in serum of four patients (IM#1, IM#2, IM#3, IM#8) with infectious mononucleosis (IM) (upper panel) and three patients (CAEBV#1, CAEBV#2, CAEBV#5) with chronic active EBV infection (CAEBV) over time after their IM (x-axis). In a and b, arbitrary optical density (O.D.) for anti-IL-27 autoAbs, complexed anti-IL-27 autoAbs and IL-27 quantifications. c, Immunoblots of recombinant IL-27 from Peprotech revealed using plasma from one healthy donor (Ctrl.), from two patients with IM (IM #1, IM #2) or from one patient carrying a STAT1 GOF mutation or anti-IL-27 p28 monoclonal antibody (MM27-7B, Biolegend) (anti-IL-27) in the right. Representative data of five independent experiments are shown. The arrows indicate the p28 subunit of recombinant IL-27 that resolves as a doublet. Size markers in kDa on the left. d, Characterization of recombinant IL-27 proteins and anti-p28 and anti-EBI3 antibodies used in this study. Immunoblots of IL-27 recombinant proteins from Peprotech and Biolegend. IL-27 was revealed using the anti-IL-27 p28 neutralizing monoclonal antibody (clone MM27-7B, Biolegend), anti-IL-27 p28 monoclonal antibody (B0315A10, Biolegend) or anti-IL-27 EBI3 (clone A15058A, Biolegend). The arrows on the left indicate the p28 (resolving as a doublet) and EBI3 subunits of IL-27 protein (Peprotech) or uncleavable recombinant IL-27 protein (EBI3+p28) (Biolegend). Size markers in kDa on the right. Data from one representative experiment of two.

Source Data

Extended Data Fig. 12 Characterization of the neutralization effect of anti-IL-27 autoAbs detected in sera of patients with IM.

a, Representative FACS histograms depicting intracellular pSTAT1 expression in healthy control T cells stimulated for 15 min with a low concentration of anti-CD3 (0.1 µg.mL−1) or not (no stim.) with IL-27 (50 ng/mL−1) or not in the presence or not of serum samples of healthy control (Ctrl.), a patient with IM, a patient carrying STAT1 GOF mutation or a blocking anti-IL-27 monoclonal antibody. One representative experiment of three independent experiments. b, Left panel, mean fluorescence intensity (MFI) from FACS analysis of intracellular pSTAT1 expression in control LCLs stimulated or not with IL-27 (5 ng/mL−1) for 15 min in the presence or not of serum samples of healthy controls (Ctrl.) (n = 5), patients with IM (n = 4) or CAEBV (n = 4). One representative experiment of three independent experiments. The horizontal bars represent the median ± s.d. of pSTAT1 MFI. Two tailed paired t tests were used. Right panel, representative FACS histograms depicting intracellular pSTAT1 expression in LCL from which MFI values were calculated and shown in the left panel. Grey histograms correspond to no stimulation, while colour lines histograms correspond to stimulation with IL-27 in the presence of control (Ctrl.), IM or a CAEBV serum sample. (c-e), Characterization of the neutralizing activity of anti-IL-27 autoAbs with representative overlaid FACS histograms showing cell divisions by CTV dye dilution of naive CD4 T cells stimulated with coated anti-CD3 (0.1 µg.ml−1) in the presence of IL-27 (50 ng.ml−1) incubated with the indicated dilution of serum (d, e), purified IgG or depleted IgG fractions from serum (c). In d, control sera from healthy donors (Ctrl.#1, Ctrl.#2) and commercial human serum (AB). In e, sera of four IM patients (IM#1, IM#2, IM#4 and IM#22). Data from one experiment. In c, depleted (line) or purified (shaded) IgG fractions of sera from a healthy control (Ctrl.) (in grey), two patients with IM#1, IM#2 (in red), on patient STAT1 GOF (in green) or blocking anti-IL27 antibody (in black). Data from one experiment.

Source Data

Extended Data Table 1 Features of patients with IM tested for anti-IL-27 AutoAbs
Full size table
Extended Data Table 2 Features of patients with CAEBV tested for anti-IL-27 AutoAbs
Full size table
Extended Data Table 3 Features of patients with STAT1 deficiency or APECED tested for anti-IL-27 AutoAbs
Full size table
Extended Data Table 4 Features of controls tested for anti-IL-27 AutoAbs
Full size table
Extended Data Table 5 List of antibodies used in flow cytometry and western blotting experiments
Full size table

Supplementary information

Supplementary Figures

Supplementary Figs. 1–3.

Reporting Summary

Source data

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Martin, E., Winter, S., Garcin, C. et al. Role of IL-27 in Epstein–Barr virus infection revealed by IL-27RA deficiency. Nature 628, 620–629 (2024). https://doi.org/10.1038/s41586-024-07213-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41586-024-07213-6

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing