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.

  • Review Article
  • Published:

Interferon-λ orchestrates innate and adaptive mucosal immune responses

Nature Reviews Immunology volume 19, pages 614–625 (2019)Cite this article

Subjects

Abstract

Type III interferon (IFN-λ) was initially thought to have functions similar to those of the type I interferons (IFN-α and IFN-β). New findings have indicated, however, that IFN-λ has a non-redundant role in the innate antiviral, antifungal and antiprotozoal defences of mucosal barriers. In this Review, we highlight recent work showing that IFN-λ inhibits virus dissemination within the body and limits the transmission of respiratory and gastrointestinal viruses to naive hosts. We also discuss findings indicating that IFN-λ can act on neutrophils to prevent invasive pulmonary aspergillosis. We summarize results showing that IFN-λ signalling differs in several respects from IFN-α and IFN-β signalling, particularly in neutrophils. Finally, we discuss new findings indicating that IFN-λ is a potent enhancer of adaptive immune responses in the respiratory mucosa.

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: Type I and type III IFN-induced signalling pathways.
Fig. 2: IFN-λ-induced production of reactive oxygen species in mouse neutrophils.
Fig. 3: IFN-λ induces innate immune defences at mucosal barriers.
Fig. 4: IFN-λ activates adaptive immune responses in the upper airways.

Similar content being viewed by others

References

  1. Kotenko, S. V. et al. IFN-λs mediate antiviral protection through a distinct class II cytokine receptor complex. Nat. Immunol. 4, 69–77 (2003).

    CAS  PubMed  Google Scholar 

  2. Sheppard, P. et al. IL-28, IL-29 and their class II cytokine receptor IL-28R. Nat. Immunol. 4, 63–68 (2003).

    CAS  PubMed  Google Scholar 

  3. Stark, G. R. & Darnell, J. E. Jr. The JAK-STAT pathway at twenty. Immunity 36, 503–514 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Ank, N. et al. An important role for type III interferon (IFN-λ/IL-28) in TLR-induced antiviral activity. J. Immunol. 180, 2474–2485 (2008).

    CAS  PubMed  Google Scholar 

  5. Andreakos, E., Zanoni, I. & Galani, I. E. Lambda interferons come to light: dual function cytokines mediating antiviral immunity and damage control. Curr. Opin. Immunol. 56, 67–75 (2018).

    PubMed  PubMed Central  Google Scholar 

  6. Best, S. M. & Robertson, S. J. IFN-λ: the key to norovirus’s secret hideaway. Cell Host Microbe 22, 427–429 (2017).

    PubMed  Google Scholar 

  7. Kotenko, S. V. & Durbin, J. E. Contribution of type III interferons to antiviral immunity: location, location, location. J. Biol. Chem. 292, 7295–7303 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Nice, T. J., Robinson, B. A. & Van Winkle, J. A. The role of interferon in persistent viral infection: insights from murine norovirus. Trends Microbiol. 26, 510–524 (2018).

    CAS  PubMed  Google Scholar 

  9. Chinnaswamy, S. Gene-disease association with human IFNL locus polymorphisms extends beyond hepatitis C virus infections. Genes Immun. 17, 265–275 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Robinson, B. A. & Nice, T. J. You can breathe easy: IFNλ handles flu without triggering a damaging inflammatory response. Immunity 46, 768–770 (2017).

    CAS  PubMed  Google Scholar 

  11. Syedbasha, M. & Egli, A. Interferon λ: modulating immunity in infectious diseases. Front. Immunol. 8, 119 (2017).

    PubMed  PubMed Central  Google Scholar 

  12. Wells, A. I. & Coyne, C. B. Type III interferons in antiviral defenses at barrier surfaces. Trends Immunol. 39, 848–858 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Zanoni, I., Granucci, F. & Broggi, A. Interferon (IFN)-λ takes the helm: immunomodulatory roles of type III IFNs. Front. Immunol. 8, 1661 (2017).

    PubMed  PubMed Central  Google Scholar 

  14. Lasfar, A., Zloza, A., Silk, A. W., Lee, L. Y. & Cohen-Solal, K. A. Interferon λ: toward a dual role in cancer. J. Interferon Cytokine Res. 39, 22–29 (2018).

    PubMed  Google Scholar 

  15. Lazear, H. M., Nice, T. J. & Diamond, M. S. Interferon-λ: immune functions at barrier surfaces and beyond. Immunity 43, 15–28 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Lee, S. & Baldridge, M. T. Interferon-λ: a potent regulator of intestinal viral infections. Front. Immunol. 8, 749 (2017).

    PubMed  PubMed Central  Google Scholar 

  17. Sun, Y., Jiang, J., Tien, P., Liu, W. & Li, J. IFN-λ: a new spotlight in innate immunity against influenza virus infection. Protein Cell 9, 832–837 (2018).

    PubMed  PubMed Central  Google Scholar 

  18. Stanifer, M. L., Pervolaraki, K. & Boulant, S. Differential regulation of type I and type III interferon signaling. Int. J. Mol. Sci. 20, E1445 (2019).

    PubMed  Google Scholar 

  19. Bruening, J., Weigel, B. & Gerold, G. The role of type III interferons in hepatitis C virus infection and therapy. J. Immunol. Res. 2017, 7232361 (2017).

    PubMed  PubMed Central  Google Scholar 

  20. Boisvert, M. & Shoukry, N. H. Type III interferons in hepatitis C virus infection. Front. Immunol. 7, 628 (2016).

    PubMed  PubMed Central  Google Scholar 

  21. Liu, B., McGilvray, I. & Chen, L. IFN-λ: a new class of interferon with distinct functions-implications for hepatitis C virus research. Gastroenterol. Res. Pract. 2015, 796461 (2015).

    PubMed  PubMed Central  Google Scholar 

  22. Olmedo, D. B., Cader, S. A. & Porto, L. C. IFN- gene polymorphisms as predictive factors in chronic hepatitis C treatment-naive patients without access to protease inhibitors. J. Med. Virol. 87, 1702–1715 (2015).

    CAS  PubMed  Google Scholar 

  23. Griffiths, S. J., Dunnigan, C. M., Russell, C. D. & Haas, J. G. The role of interferon-λ locus polymorphisms in hepatitis C and other infectious diseases. J. Innate Immun. 7, 231–242 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Mihm, S. Activation of type I and type III interferons in chronic hepatitis C. J. Innate Immun. 7, 251–259 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Sommereyns, C., Paul, S., Staeheli, P. & Michiels, T. IFN-λ (IFN-λ) is expressed in a tissue-dependent fashion and primarily acts on epithelial cells in vivo. PLOS Pathog. 4, e1000017 (2008).

    PubMed  PubMed Central  Google Scholar 

  26. Reuter, A. et al. Antiviral activity of λ interferon in chickens. J. Virol. 88, 2835–2843 (2014).

    PubMed  PubMed Central  Google Scholar 

  27. Gurney, A. L. IL-22, a Th1 cytokine that targets the pancreas and select other peripheral tissues. Int. Immunopharmacol. 4, 669–677 (2004).

    CAS  PubMed  Google Scholar 

  28. Espinosa, V. et al. Type III interferon is a critical regulator of innate antifungal immunity. Sci. Immunol. 2, eaan5357 (2017). This study highlights the importance of IFN-λ during antifungal immunity and shows that neutrophils have a key role in the response.

    PubMed  PubMed Central  Google Scholar 

  29. Chiriac, M. T. et al. Activation of epithelial signal transducer and activator of transcription 1 by interleukin 28 controls mucosal healing in mice with colitis and is increased in mucosa of patients with inflammatory bowel disease. Gastroenterology 153, 123–138 (2017).

    CAS  PubMed  Google Scholar 

  30. Selvakumar, T. A. et al. Identification of a predominantly interferon-λ-induced transcriptional profile in murine intestinal epithelial cells. Front. Immunol. 8, 1302 (2017).

    PubMed  PubMed Central  Google Scholar 

  31. Ding, S., Khoury-Hanold, W., Iwasaki, A. & Robek, M. D. Epigenetic reprogramming of the type III interferon response potentiates antiviral activity and suppresses tumor growth. PLOS Biol. 12, e1001758 (2014).

    PubMed  PubMed Central  Google Scholar 

  32. Mahlakoiv, T., Hernandez, P., Gronke, K., Diefenbach, A. & Staeheli, P. Leukocyte-derived IFN-α/beta and epithelial IFN-λ constitute a compartmentalized mucosal defense system that restricts enteric virus infections. PLOS Pathog. 11, e1004782 (2015). This article shows that type I and type III IFNs act on separate cell types in the intestinal mucosa.

    PubMed  PubMed Central  Google Scholar 

  33. Mordstein, M. et al. Interferon-λ contributes to innate immunity of mice against influenza A virus but not against hepatotropic viruses. PLOS Pathog. 4, e1000151 (2008).

    PubMed  PubMed Central  Google Scholar 

  34. Mordstein, M. et al. Lambda interferon renders epithelial cells of the respiratory and gastrointestinal tracts resistant to viral infections. J. Virol. 84, 5670–5677 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Wack, A., Terczynska-Dyla, E. & Hartmann, R. Guarding the frontiers: the biology of type III interferons. Nat. Immunol. 16, 802–809 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Klinkhammer, J. et al. IFN-λ prevents influenza virus spread from the upper airways to the lungs and limits virus transmission. eLife 7, e33354 (2018). This study shows that IFN-λ has a previously overlooked role in the upper airways, where it reduces viral transmission and the spread of respiratory viruses to the lungs.

    PubMed  PubMed Central  Google Scholar 

  37. Odom, D. T. et al. Tissue-specific transcriptional regulation has diverged significantly between human and mouse. Nat. Genet. 39, 730–732 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Dickensheets, H., Sheikh, F., Park, O., Gao, B. & Donnelly, R. P. Interferon-λ (IFN-λ) induces signal transduction and gene expression in human hepatocytes, but not in lymphocytes or monocytes. J. Leukoc. Biol. 93, 377–385 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Diegelmann, J. et al. Comparative analysis of the λ-interferons IL-28A and IL-29 regarding their transcriptome and their antiviral properties against hepatitis C virus. PLOS ONE 5, e15200 (2010).

    PubMed  PubMed Central  Google Scholar 

  40. Doyle, S. E. et al. Interleukin-29 uses a type 1 interferon-like program to promote antiviral responses in human hepatocytes. Hepatology 44, 896–906 (2006).

    CAS  PubMed  Google Scholar 

  41. Lind, K., Svedin, E., Utorova, R., Stone, V. M. & Flodstrom-Tullberg, M. Type III interferons are expressed by Coxsackievirus-infected human primary hepatocytes and regulate hepatocyte permissiveness to infection. Clin. Exp. Immunol. 177, 687–695 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Muir, A. J. et al. Phase 1b study of pegylated interferon λ 1 with or without ribavirin in patients with chronic genotype 1 hepatitis C virus infection. Hepatology 52, 822–832 (2010).

    CAS  PubMed  Google Scholar 

  43. Hermant, P. et al. Human but not mouse hepatocytes respond to interferon-λ in vivo. PLOS ONE 9, e87906 (2014).

    PubMed  PubMed Central  Google Scholar 

  44. Lion, A. et al. Chicken endothelial cells are highly responsive to viral innate immune stimuli and are susceptible to infections with various avian pathogens. Avian Pathol. 48, 121–134 (2018).

    Google Scholar 

  45. Lazear, H. M. et al. Interferon-λ restricts West Nile virus neuroinvasion by tightening the blood-brain barrier. Sci. Transl Med. 7, 284ra259 (2015).

    Google Scholar 

  46. Douam, F. et al. Type III interferon-mediated signaling is critical for controlling live attenuated yellow fever virus infection in vivo. mBio 8, e0081917 (2017).

    Google Scholar 

  47. Kelly, A. et al. Immune cell profiling of IFN- response shows pDCs express highest level of IFN-R1 and are directly responsive via the JAK-STAT pathway. J. Interferon Cytokine Res. 36, 671–680 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. de Groen, R. A., Groothuismink, Z. M. A., Liu, B. S. & Boonstra, A. IFN-λ is able to augment TLR-mediated activation and subsequent function of primary human B cells. J. Leukoc. Biol. 98, 623–630 (2015).

    PubMed  Google Scholar 

  49. Witte, K. et al. Despite IFN-λ receptor expression, blood immune cells, but not keratinocytes or melanocytes, have an impaired response to type III interferons: implications for therapeutic applications of these cytokines. Genes Immun. 10, 702–714 (2009).

    CAS  PubMed  Google Scholar 

  50. Novak, A. J. et al. A role for IFN-λ 1 in multiple myeloma B cell growth. Leukemia 22, 2240–2246 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Egli, A. et al. IL-28B is a key regulator of B− and T cell vaccine responses against influenza. PLOS Pathog. 10, e1004556 (2014).

    PubMed  PubMed Central  Google Scholar 

  52. Broggi, A., Tan, Y., Granucci, F. & Zanoni, I. IFN-λ suppresses intestinal inflammation by non-translational regulation of neutrophil function. Nat. Immunol. 18, 1084–1093 (2017). This paper reports that IFN-λ can modulate neutrophil activity through non-conventional signalling pathways that involve the kinase JAK2.

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Galani, I. E. et al. Interferon-λ mediates non-redundant front-line antiviral protection against influenza virus infection without compromising host fitness. Immunity 46, 875–890 (2017). This study contributes evidence that IFN-λ has a decisive role in antiviral defence of the respiratory tract by acting on airway epithelial cells and neutrophils.

    CAS  PubMed  Google Scholar 

  54. Ye, L. et al. Interferon-λ enhances adaptive mucosal immunity by boosting release of thymic stromal lymphopoietin. Nat. Immunol. 20, 593–601 (2019). This study indicates a novel mechanism by which IFN-λ can increase adaptive antiviral immunity in the respiratory mucosa.

    CAS  PubMed  Google Scholar 

  55. Blazek, K. et al. IFN-λ resolves inflammation via suppression of neutrophil infiltration and IL-1beta production. J. Exp. Med. 212, 845–853 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Yin, Z. et al. Type III IFNs are produced by and stimulate human plasmacytoid dendritic cells. J. Immunol. 189, 2735–2745 (2012).

    CAS  PubMed  Google Scholar 

  57. Megjugorac, N. J., Gallagher, G. E. & Gallagher, G. Modulation of human plasmacytoid DC function by IFN-λ 1 (IL-29). J. Leukoc. Biol. 86, 1359–1363 (2009).

    CAS  PubMed  Google Scholar 

  58. Mennechet, F. J. D. & Uze, G. Interferon-λ-treated dendritic cells specifically induce proliferation of FOXP3-expressing suppressor T cells. Blood 107, 4417–4423 (2006).

    CAS  PubMed  Google Scholar 

  59. Finotti, G., Tamassia, N., Calzetti, F., Fattovich, G. & Cassatella, M. A. Endogenously produced TNF-α contributes to the expression of CXCL10/IP-10 in IFN-λ 3-activated plasmacytoid dendritic cells. J. Leukoc. Biol. 99, 107–119 (2016).

    CAS  PubMed  Google Scholar 

  60. O’Connor, K. S. et al. IFNL3 mediates interaction between innate immune cells: Implications for hepatitis C virus pathogenesis. Innate Immun. 20, 598–605 (2014).

    PubMed  Google Scholar 

  61. Jordan, W. J. et al. Modulation of the human cytokine response by interferon λ-1 (IFN-λ1/IL-29). Genes Immun. 8, 13–20 (2007).

    CAS  PubMed  Google Scholar 

  62. Souza-Fonseca-Guimaraes, F. et al. NK cells require IL-28R for optimal in vivo activity. Proc. Natl Acad. Sci. USA 112, E2376–E2384 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Brias, S. G. et al. Interferon λ is required for interferon γ-expressing NK cell responses but does not afford antiviral protection during acute and persistent murine cytomegalovirus infection. PLOS ONE 13, e0197596 (2018).

    Google Scholar 

  64. Morrison, M. H. et al. IFNL cytokines do not modulate human or murine NK cell functions. Hum. Immunol. 75, 996–1000 (2014).

    CAS  PubMed  Google Scholar 

  65. Wang, Y. S. et al. Involvement of NK cells in IL-28B-mediated immunity against influenza virus infection. J. Immunol. 199, 1012–1020 (2017).

    CAS  PubMed  Google Scholar 

  66. Liu, B. S., Janssen, H. L. A. & Boonstra, A. IL-29 and IFN α differ in their ability to modulate IL-12 production by TLR-activated human macrophages and exhibit differential regulation of the IFN γ receptor expression. Blood 117, 2385–2395 (2011).

    CAS  PubMed  Google Scholar 

  67. Liu, M. Q. et al. IFN-λ3 inhibits HIV infection of macrophages through the JAK-STAT pathway. PLOS ONE 7, e35902 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Su, Q. J. et al. IFN-λ4 inhibits HIV infection of macrophages through signaling of IFN-λR1/IL-10R2 receptor complex. Scand. J. Immunol. 88, e12717 (2018).

    PubMed  PubMed Central  Google Scholar 

  69. Lumb, J. H. et al. DDX6 represses aberrant activation of interferon-stimulated genes. Cell Rep. 20, 819–831 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Fuchs, S. et al. Tyrosine kinase 2 is not limiting human antiviral type III interferon responses. Eur. J. Immunol. 46, 2639–2649 (2016).

    CAS  PubMed  Google Scholar 

  71. Kreins, A. Y. et al. Human TYK2 deficiency: mycobacterial and viral infections without hyper-IgE syndrome. J. Exp. Med. 212, 1641–1662 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Odendall, C. et al. Diverse intracellular pathogens activate type III interferon expression from peroxisomes. Nat. Immunol. 15, 717–726 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Lee, S. J., Kim, W. J. & Moon, S. K. Role of the p38 MAPK signaling pathway in mediating interleukin-28A-induced migration of UMUC-3 cells. Int. J. Mol. Med. 30, 945–952 (2012).

    CAS  PubMed  Google Scholar 

  74. Schnepf, D. & Staeheli, P. License to kill: IFN-λ regulates antifungal activity of neutrophils. Sci. Immunol. 2, eaap9614 (2017).

    PubMed  Google Scholar 

  75. Pervolaraki, K. et al. Type I and type III interferons display different dependency on mitogen-activated protein kinases to mount an antiviral state in the human gut. Front. Immunol. 8, 459 (2017). This study shows that non-canonical MAPK signalling is required for full antiviral protection of human intestinal epithelial cells induced by type III IFN but not by type I IFN.

    PubMed  PubMed Central  Google Scholar 

  76. Pervolaraki, K. et al. Differential induction of interferon stimulated genes between type I and type III interferons is independent of interferon receptor abundance. PLOS Pathog. 14, e1007420 (2018).

    PubMed  PubMed Central  Google Scholar 

  77. Crotta, S. et al. Type I and type III interferons drive redundant amplification loops to induce a transcriptional signature in influenza-infected airway epithelia. PLOS Pathog. 9, e1003773 (2013).

    PubMed  PubMed Central  Google Scholar 

  78. Arimoto, K. I., Miyauchi, S., Stoner, S. A., Fan, J. B. & Zhang, D. E. Negative regulation of type I IFN signaling. J. Leukoc. Biol. 103, 1099–1116 (2018).

    CAS  Google Scholar 

  79. Malakhova, O. A. et al. UBP43 is a novel regulator of interferon signaling independent of its ISG15 isopeptidase activity. EMBO J. 25, 2358–2367 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Blumer, T., Coto-Llerena, M., Duong, F. H. T. & Heim, M. H. SOCS1 is an inducible negative regulator of interferon λ (IFN-λ)-induced gene expression in vivo. J. Biol. Chem. 292, 17928–17938 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  81. Piganis, R. A. et al. Suppressor of cytokine signaling (SOCS) 1 inhibits type I interferon (IFN) signaling via the interferon α receptor (IFNAR1)-associated tyrosine kinase Tyk2. J. Biol. Chem. 286, 33811–33818 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Davidson, S. et al. IFNλ is a potent anti-influenza therapeutic without the inflammatory side effects of IFNα treatment. EMBO Mol. Med. 8, 1099–1112 (2016). This article introduces the concept that IFN-λ might be a better therapeutic anti-influenza drug than type I IFN.

    CAS  PubMed  PubMed Central  Google Scholar 

  83. Pott, J. et al. IFN-λ determines the intestinal epithelial antiviral host defense. Proc. Natl Acad. Sci. USA 108, 7944–7949 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Lin, J. D. et al. Distinct roles of type I and type III interferons in intestinal immunity to homologous and heterologous rotavirus infections. PLOS Pathog. 12, e1005600 (2016).

    PubMed  PubMed Central  Google Scholar 

  85. Wilen, C. B. et al. Tropism for tuft cells determines immune promotion of norovirus pathogenesis. Science 360, 204–208 (2018). This study shows that norovirus persists in tuft cells and that IFN-λ treatment of mice eliminates the virus from this reservoir.

    CAS  PubMed  PubMed Central  Google Scholar 

  86. Nice, T. J. et al. Interferon-λ cures persistent murine norovirus infection in the absence of adaptive immunity. Science 347, 269–273 (2015).

    CAS  PubMed  Google Scholar 

  87. Rocha-Pereira, J. et al. Interferon λ (IFN-λ) efficiently blocks norovirus transmission in a mouse model. Antiviral Res. 149, 7–15 (2018).

    CAS  PubMed  Google Scholar 

  88. Ingle, H. et al. Viral complementation of immunodeficiency confers protection against enteric pathogens via interferon-λ. Nat. Microbiol. https://doi.org/10.1038/s41564-019-0416-7 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  89. Good, C., Wells, A. I. & Coyne, C. B. Type III interferon signaling restricts enterovirus 71 infection of goblet cells. Sci. Adv. 5, eaau4255 (2019).

    PubMed  PubMed Central  Google Scholar 

  90. Ferguson, S. H. et al. Interferon-λ3 promotes epithelial defense and barrier function against Cryptosporidium parvum infection. Cell. Mol. Gastroenterol. Hepatol. 8, 1–20 (2019). This article shows that IFN-λ is also involved in host defence against infection with protozoal parasites.

    PubMed  PubMed Central  Google Scholar 

  91. Odendall, C., Voak, A. A. & Kagan, J. C. Type III IFNs are commonly induced by bacteria-sensing TLRs and reinforce epithelial barriers during infection. J. Immunol. 199, 3270–3279 (2017).

    CAS  PubMed  Google Scholar 

  92. Haller, O., Staeheli, P., Schwemmle, M. & Kochs, G. Mx GTPases: dynamin-like antiviral machines of innate immunity. Trends Microbiol. 23, 154–163 (2015).

    CAS  PubMed  Google Scholar 

  93. Okabayashi, T. et al. Type-III interferon, not type-I, is the predominant interferon induced by respiratory viruses in nasal epithelial cells. Virus Res. 160, 360–366 (2011).

    CAS  PubMed  Google Scholar 

  94. Jewell, N. A. et al. Lambda interferon is the predominant interferon induced by influenza A virus infection in vivo. J. Virol. 84, 11515–11522 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  95. Werder, R. B. et al. PGD2/DP2 receptor activation promotes severe viral bronchiolitis by suppressing IFN-λ production. Sci. Transl Med. 10, eaao0052 (2018).

    PubMed  Google Scholar 

  96. Cohen, T. S. & Prince, A. S. Bacterial pathogens activate a common inflammatory pathway through IFNλ regulation of PDCD4. PLOS Pathog. 9, e1003682 (2013).

    PubMed  PubMed Central  Google Scholar 

  97. Pires, S. & Parker, D. IL-1beta activation in response to Staphylococcus aureus lung infection requires inflammasome-dependent and independent mechanisms. Eur. J. Immunol. 48, 1707–1716 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  98. Ahn, D., Wickersham, M., Riquelme, S. & Prince, A. The effects of IFN-λ on epithelial barrier function contribute to K. pneumoniae ST258 pneumonia. Am. J. Respir. Cell. Mol. Biol. 60, 158–166 (2018).

    Google Scholar 

  99. Rich, H. E. et al. Interferon λ inhibits bacterial uptake during influenza superinfection. Infect. Immun. 87, e00114–19 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  100. Caine, E. A. et al. Interferon λ protects the female reproductive tract against Zika virus infection. Nat. Commun. 10, 280 (2019).

    PubMed  PubMed Central  Google Scholar 

  101. Wira, C. R., Rodriguez-Garcia, M. & Patel, M. V. The role of sex hormones in immune protection of the female reproductive tract. Nat. Rev. Immunol. 15, 217–230 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  102. Fuertes, M. B., Woo, S. R., Burnett, B., Fu, Y. X. & Gajewski, T. F. Type I interferon response and innate immune sensing of cancer. Trends Immunol. 34, 67–73 (2013).

    CAS  PubMed  Google Scholar 

  103. Misumi, I. & Whitmire, J. K. IFN-λ exerts opposing effects on T cell responses depending on the chronicity of the virus infection. J. Immunol. 192, 3596–3606 (2014).

    CAS  PubMed  Google Scholar 

  104. Garcia-Sastre, A. et al. Influenza A virus lacking the NS1 gene replicates in interferon-deficient systems. Virology 252, 324–330 (1998).

    CAS  PubMed  Google Scholar 

  105. Morokutti, A., Muster, T. & Ferko, B. Intranasal vaccination with a replication-deficient influenza virus induces heterosubtypic neutralising mucosal IgA antibodies in humans. Vaccine 32, 1897–1900 (2014).

    CAS  PubMed  Google Scholar 

  106. Mossler, C. et al. Phase I/II trial of a replication-deficient trivalent influenza virus vaccine lacking NS1. Vaccine 31, 6194–6200 (2013).

    PubMed  Google Scholar 

  107. Morrow, M. P. et al. Comparative ability of IL-12 and IL-28B to regulate Treg populations and enhance adaptive cellular immunity. Blood 113, 5868–5877 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  108. Zhou, Y. et al. Optimized DNA vaccine enhanced by adjuvant IL28B induces protective immune responses against herpes simplex virus type 2 in mice. Viral Immunol. 30, 601–614 (2017).

    CAS  PubMed  Google Scholar 

  109. Morrow, M. P. et al. IL-28B/IFN-λ3 drives granzyme B loading and significantly increases CTL killing activity in macaques. Mol. Ther. 18, 1714–1723 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  110. Morrow, M. P. et al. Unique Th1/Th2 phenotypes induced during priming and memory phases by use of interleukin-12 (IL-12) or IL-28B vaccine adjuvants in Rhesus Macaques. Clin. Vaccine Immunol. 17, 1493–1499 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  111. Baldridge, M. T. et al. Expression of Ifnlr1 on intestinal epithelial cells is critical to the antiviral effects of interferon λ against norovirus and reovirus. J. Virol. 91, e0207916 (2017).

    Google Scholar 

  112. Koltsida, O. et al. IL-28A (IFN-λ 2) modulates lung DC function to promote Th1 immune skewing and suppress allergic airway disease. EMBO Mol. Med. 3, 348–361 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  113. Kramer, B. et al. Do λ-IFNs IL28A and IL28B act on human natural killer cells? Proc. Natl Acad. Sci. USA 108, E519–E520 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  114. de Groen, R. A. et al. IFN-λ-mediated IL-12 production in macrophages induces IFN-γ production in human NK cells. Eur. J. Immunol. 45, 250–259 (2015).

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors thank O. Haller for constructive comments on this article. Funding for the work carried out in the laboratory of the authors was provided by the European Union’s Seventh Framework Program, grant agreement 607690, and the Deutsche Forschungsgemeinschaft, grant agreement STA 338/15-1.

Peer review information

Nature Reviews Immunology thanks S. Boulant, S. V. Kotenko and other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Author information

Author notes

  1. These authors contributed equally: Liang Ye, Daniel Schnepf

Authors and Affiliations

  1. Institute of Virology, Medical Center University of Freiburg, Freiburg, Germany

    Liang Ye, Daniel Schnepf & Peter Staeheli

  2. Spemann Graduate School of Biology and Medicine (SGBM), Albert Ludwigs University Freiburg, Freiburg, Germany

    Daniel Schnepf

  3. Medical Faculty, University of Freiburg, Freiburg, Germany

    Peter Staeheli

Authors
  1. Liang Ye
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Daniel Schnepf
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Peter Staeheli
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

The authors contributed equally to all aspects of the article.

Corresponding author

Correspondence to Peter Staeheli.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note

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

Glossary

Janus kinase family

(JAK family). JAK1, JAK2, JAK3 and tyrosine kinase 2 (TYK2) are non-receptor tyrosine kinases associated with class I and class II cytokine receptors that are responsible for signal transduction through the phosphorylation of signal transducer and activator of transcription (STAT) family members.

Signal transducer and activator of transcription

(STAT). STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B and STAT6 are transcription factors that are activated by Janus kinases to transduce the signal from class I and class II cytokine receptors. Type I and type III interferons (IFNs) mainly induce the activation of STAT1–STAT2 heterodimers, which form a complex with IFN response factor 9 (IRF9), known as IFN-stimulated gene factor 3 (ISGF3). Type II IFN (IFN-γ) mainly induces the activation of STAT1 homodimers.

Interferon-stimulated gene factor 3

(ISGF3). A complex consisting of STAT1–STAT2 heterodimers, together with interferon (IFN) response factor 9 (IRF9). ISGF3 binds to IFN-stimulated response elements (ISREs) in the promoter regions of IFN-stimulated genes to regulate transcriptional activity.

Interferon-stimulated response element

(ISRE). A sequence element in the promoter regions of interferon-stimulated genes (ISGs) that is recognized by ISG factor 3 (ISGF3) to regulate transcriptional activity.

Interferon-stimulated genes

(ISGs). The transcriptional activity of ISGs is regulated by interferon-induced Janus kinase–signal transducer and activator of transcription (JAK–STAT) signalling. ISGs can contain one or more interferon-stimulated response element (ISRE) and/or gamma-activated sequence element in their promoter regions. Some ISGs are also regulated by other transcription factors (such as nuclear factor-κB).

Dextran sodium sulfate-induced colitis

Dextran sodium sulfate can be provided in drinking water to chemically induce intestinal inflammation as a model for inflammatory bowel diseases in mice. This treatment disrupts the epithelial integrity in the colon and subsequently leads to dissemination of the luminal contents to the underlying tissue.

Blood–brain barrier

A selective, semipermeable barrier that separates the central nervous system from the circulating blood. It is formed by tight-junction connections of endothelial cells, astrocytic end-feet and pericytes.

HAP1 cells

A near-haploid cell line derived from the male chronic myelogenous leukaemia cell line KBM-7. Owing to their near-haploid karyotype, HAP1 cells are frequently used to generate CRISPR–Cas-mediated knockouts or to carry out genome-wide mutagenesis studies.

Tuft cells

Specialized epithelial cells located in various mucosal tissues that can detect allergens or parasitic pathogens through chemical-sensing (taste) receptors. They release IL-25 to promote immune cell infiltration, mucus production, muscle contraction and tissue repair.

Microfold cells

(M cells). Specialized epithelial cells located in mucosal tissues, such as the intestine or respiratory tract, that provide antigens from the exterior environment to macrophages or dendritic cells through transcytosis in order to initiate an immune response.

Ifnlr1 tm1b mice

A mouse strain that harbours a LacZ-tagged null allele under the control of the endogenous Ifnlr1 promoter. Tissue-specific expression of Ifnlr1 can be visualized by β-galactosidase staining.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ye, L., Schnepf, D. & Staeheli, P. Interferon-λ orchestrates innate and adaptive mucosal immune responses. Nat Rev Immunol 19, 614–625 (2019). https://doi.org/10.1038/s41577-019-0182-z

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41577-019-0182-z

This article is cited by

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