Effector T cells control lung inflammation during acute influenza virus infection by producing IL-10


Activated antigen-specific T cells produce a variety of effector molecules for clearing infection but also contribute to inflammation and tissue injury. Here we report an anti-inflammatory property of antiviral CD8+ and CD4+ effector T cells (Teff cells) in the infected periphery during acute virus infection. We find that, during acute influenza infection, interleukin-10 (IL-10) is produced in the infected lungs in large amounts—exclusively by infiltrating virus-specific Teff cells, with CD8+ Teff cells contributing a larger fraction of the IL-10 produced. These Teff cells in the periphery simultaneously produce IL-10 and proinflammatory cytokines and express lineage markers characteristic of conventional T helper type 1 or T cytotoxic type 1 cells. Notably, blocking the action of the Teff cell–derived IL-10 results in enhanced pulmonary inflammation and lethal injury. Our results show that antiviral Teff cells exert regulatory functions—that is, they fine-tune the extent of lung inflammation and injury associated with influenza infection by producing an anti-inflammatory cytokine. We discuss the potential implications of these findings for infection with highly pathogenic influenza viruses.

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Figure 1: Influenza-specific T cells preferentially produce IL-10 and IFN-γ in the influenza-infected BALB/c lungs.
Figure 2: IL-10–producing CD8+ and CD4+ T cells are type 1 effectors.
Figure 3: Kinetics of IL-10–producing CD8+ and CD4+ Teff cells in vivo. BALB/c mice were infected with influenza.
Figure 4: Teff cells are the major source of IL-10 in vivo during influenza infection.
Figure 5: IL-10R blockade in vivo results in increased mortality and accelerated death during influenza infection.
Figure 6: IL-10R blockade leads to lethal pulmonary inflammation during influenza infection.


  1. 1

    Cheung, C.Y. et al. Induction of proinflammatory cytokines in human macrophages by influenza A (H5N1) viruses: a mechanism for the unusual severity of human disease? Lancet 360, 1831–1837 (2002).

  2. 2

    de Jong, M.D. et al. Fatal outcome of human influenza A (H5N1) is associated with high viral load and hypercytokinemia. Nat. Med. 12, 1203–1207 (2006).

  3. 3

    Kobasa, D. et al. Aberrant innate immune response in lethal infection of macaques with the 1918 influenza virus. Nature 445, 319–323 (2007).

  4. 4

    Moore, K.W., de Waal Malefyt, R., Coffman, R.L. & O'Garra, A. Interleukin-10 and the interleukin-10 receptor. Annu. Rev. Immunol. 19, 683–765 (2001).

  5. 5

    Couper, K.N., Blount, D.G. & Riley, E.M. IL-10: The master regulator of immunity to infection. J. Immunol. 180, 5771–5777 (2008).

  6. 6

    Ejrnaes, M. et al. Resolution of a chronic viral infection after interleukin-10 receptor blockade. J. Exp. Med. 203, 2461–2472 (2006).

  7. 7

    Brooks, D.G. et al. Interleukin-10 determines viral clearance or persistence in vivo. Nat. Med. 12, 1301–1309 (2006).

  8. 8

    Humphreys, I.R. et al. Cytomegalovirus exploits IL-10–mediated immune regulation in the salivary glands. J. Exp. Med. 204, 1217–1225 (2007).

  9. 9

    Maynard, C.L. et al. Regulatory T cells expressing interleukin 10 develop from Foxp3+ and Foxp3 precursor cells in the absence of interleukin 10. Nat. Immunol. 8, 931–941 (2007).

  10. 10

    O'Garra, A. & Vieira, P. TH1 cells control themselves by producing interleukin-10. Nat. Rev. Immunol. 7, 425–428 (2007).

  11. 11

    Jankovic, D. et al. Conventional T-bet+Foxp3 TH1 cells are the major source of host-protective regulatory IL-10 during intracellular protozoan infection. J. Exp. Med. 204, 273–283 (2007).

  12. 12

    Anderson, C.F., Oukka, M., Kuchroo, V.J. & Sacks, D. CD4+CD25Foxp3 TH1 cells are the source of IL-10–mediated immune suppression in chronic cutaneous leishmaniasis. J. Exp. Med. 204, 285–297 (2007).

  13. 13

    Groux, H. et al. A CD4+ T-cell subset inhibits antigen-specific T-cell responses and prevents colitis. Nature 389, 737–742 (1997).

  14. 14

    Stock, P. et al. Induction of T helper type 1–like regulatory cells that express Foxp3 and protect against airway hyper-reactivity. Nat. Immunol. 5, 1149–1156 (2004).

  15. 15

    Yoon, H., Legge, K.L., Sung, S.S. & Braciale, T.J. Sequential activation of CD8+ T cells in the draining lymph nodes in response to pulmonary virus infection. J. Immunol. 179, 391–399 (2007).

  16. 16

    Lawrence, C.W. & Braciale, T.J. Activation, differentiation, and migration of naive virus-specific CD8+ T cells during pulmonary influenza virus infection. J. Immunol. 173, 1209–1218 (2004).

  17. 17

    Lawrence, C.W., Ream, R.M. & Braciale, T.J. Frequency, specificity, and sites of expansion of CD8+ T cells during primary pulmonary influenza virus infection. J. Immunol. 174, 5332–5340 (2005).

  18. 18

    Tanchot, C. et al. Modifications of CD8+ T cell function during in vivo memory or tolerance induction. Immunity 8, 581–590 (1998).

  19. 19

    Endharti, A.T. et al. Cutting edge: CD8+CD122+ regulatory T cells produce IL-10 to suppress IFN-γ production and proliferation of CD8+ T cells. J. Immunol. 175, 7093–7097 (2005).

  20. 20

    Noble, A., Giorgini, A. & Leggat, J.A. Cytokine-induced IL-10–secreting CD8 T cells represent a phenotypically distinct suppressor T-cell lineage. Blood 107, 4475–4483 (2006).

  21. 21

    Stumhofer, J.S. et al. Interleukins 27 and 6 induce STAT3-mediated T cell production of interleukin 10. Nat. Immunol. 8, 1363–1371 (2007).

  22. 22

    Smith, T.R. & Kumar, V. Revival of CD8+ Treg-mediated suppression. Trends Immunol. 29, 337–342 (2008).

  23. 23

    Sarawar, S.R. & Doherty, P.C. Concurrent production of interleukin-2, interleukin-10, and γ interferon in the regional lymph nodes of mice with influenza pneumonia. J. Virol. 68, 3112–3119 (1994).

  24. 24

    Doyle, A.G., Buttigieg, K., Groves, P., Johnson, B.J. & Kelso, A. The activated type 1-polarized CD8+ T cell population isolated from an effector site contains cells with flexible cytokine profiles. J. Exp. Med. 190, 1081–1092 (1999).

  25. 25

    Belz, G.T., Wodarz, D., Diaz, G., Nowak, M.A. & Doherty, P.C. Compromised influenza virus-specific CD8+ T-cell memory in CD4+ T-cell–deficient mice. J. Virol. 76, 12388–12393 (2002).

  26. 26

    Shedlock, D.J. et al. Role of CD4 T cell help and costimulation in CD8 T cell responses during Listeria monocytogenes infection. J. Immunol. 170, 2053–2063 (2003).

  27. 27

    Donnelly, R.P., Dickensheets, H. & Finbloom, D.S. The interleukin-10 signal transduction pathway and regulation of gene expression in mononuclear phagocytes. J. Interferon Cytokine Res. 19, 563–573 (1999).

  28. 28

    Lin, K.L., Suzuki, Y., Nakano, H., Ramsburg, E. & Gunn, M.D. CCR2+ monocyte-derived dendritic cells and exudate macrophages produce influenza-induced pulmonary immune pathology and mortality. J. Immunol. 180, 2562–2572 (2008).

  29. 29

    Hatta, M., Gao, P., Halfmann, P. & Kawaoka, Y. Molecular basis for high virulence of Hong Kong H5N1 influenza A viruses. Science 293, 1840–1842 (2001).

  30. 30

    Tumpey, T.M. et al. Pathogenicity of influenza viruses with genes from the 1918 pandemic virus: functional roles of alveolar macrophages and neutrophils in limiting virus replication and mortality in mice. J. Virol. 79, 14933–14944 (2005).

  31. 31

    Legge, K.L. & Braciale, T.J. Lymph node dendritic cells control CD8+ T cell responses through regulated FasL expression. Immunity 23, 649–659 (2005).

  32. 32

    Barnes, P.J. & Adcock, I.M. How do corticosteroids work in asthma? Ann. Intern. Med. 139, 359–370 (2003).

  33. 33

    Lutz, M.B. et al. An advanced culture method for generating large quantities of highly pure dendritic cells from mouse bone marrow. J. Immunol. Methods 223, 77–92 (1999).

  34. 34

    Sun, J. & Pearce, E.J. Suppression of early IL-4 production underlies the failure of CD4 T cells activated by TLR-stimulated dendritic cells to differentiate into Th2 cells. J. Immunol. 178, 1635–1644 (2007).

  35. 35

    Alter, G., Malenfant, J.M. & Altfeld, M. CD107a as a functional marker for the identification of natural killer cell activity. J. Immunol. Methods 294, 15–22 (2004).

  36. 36

    Liu, F. & Whitton, J.L. Cutting edge: re-evaluating the in vivo cytokine responses of CD8+ T cells during primary and secondary viral infections. J. Immunol. 174, 5936–5940 (2005).

  37. 37

    Jelley-Gibbs, D.M. et al. Persistent depots of influenza antigen fail to induce a cytotoxic CD8 T cell response. J. Immunol. 178, 7563–7570 (2007).

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We thank M. Hufford and T. Kim for critical comments and B. Small and S. Gill for excellent technical assistance. This work was supported by the US National Institutes of Health (grants AI-15608, HL-33391 and AI37293 to T.J.B. and AI057992 to C.L.K.).

Author information

J.S. performed the experimental work and T.J.B. supervised the project. R.M. and C.L.K. provided Vert-X mice for the study. The manuscript was written by J.S. and T.J.B. All authors approved the final manuscript.

Correspondence to Thomas J Braciale.

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Sun, J., Madan, R., Karp, C. et al. Effector T cells control lung inflammation during acute influenza virus infection by producing IL-10. Nat Med 15, 277–284 (2009). https://doi.org/10.1038/nm.1929

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