Interferon-λ orchestrates innate and adaptive mucosal immune responses


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.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

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.


  1. 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).

  2. 2.

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

  3. 3.

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

  4. 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).

  5. 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).

  6. 6.

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

  7. 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).

  8. 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).

  9. 9.

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

  10. 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).

  11. 11.

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

  12. 12.

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

  13. 13.

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

  14. 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).

  15. 15.

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

  16. 16.

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

  17. 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).

  18. 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).

  19. 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).

  20. 20.

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

  21. 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).

  22. 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).

  23. 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).

  24. 24.

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

  25. 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).

  26. 26.

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

  27. 27.

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

  28. 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.

  29. 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).

  30. 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).

  31. 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).

  32. 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.

  33. 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).

  34. 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).

  35. 35.

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

  36. 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.

  37. 37.

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

  38. 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).

  39. 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).

  40. 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).

  41. 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).

  42. 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).

  43. 43.

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

  44. 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).

  45. 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).

  46. 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).

  47. 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).

  48. 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).

  49. 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).

  50. 50.

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

  51. 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).

  52. 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.

  53. 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.

  54. 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.

  55. 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).

  56. 56.

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

  57. 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).

  58. 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).

  59. 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).

  60. 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).

  61. 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).

  62. 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).

  63. 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).

  64. 64.

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

  65. 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).

  66. 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).

  67. 67.

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

  68. 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).

  69. 69.

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

  70. 70.

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

  71. 71.

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

  72. 72.

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

  73. 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).

  74. 74.

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

  75. 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.

  76. 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).

  77. 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).

  78. 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).

  79. 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).

  80. 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).

  81. 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).

  82. 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.

  83. 83.

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

  84. 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).

  85. 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.

  86. 86.

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

  87. 87.

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

  88. 88.

    Ingle, H. et al. Viral complementation of immunodeficiency confers protection against enteric pathogens via interferon-λ. Nat. Microbiol. (2019).

  89. 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).

  90. 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.

  91. 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).

  92. 92.

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

  93. 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).

  94. 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).

  95. 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).

  96. 96.

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

  97. 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).

  98. 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).

  99. 99.

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

  100. 100.

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

  101. 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).

  102. 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).

  103. 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).

  104. 104.

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

  105. 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).

  106. 106.

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

  107. 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).

  108. 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).

  109. 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).

  110. 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).

  111. 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).

  112. 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).

  113. 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).

  114. 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).

Download references


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




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.


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

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).

Download citation

Further reading