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Adaptive immune cells temper initial innate responses

Nature Medicine volume 13, pages 12481252 (2007) | Download Citation



Toll-like receptors (TLRs) recognize conserved microbial structures called pathogen-associated molecular patterns. Signaling from TLRs leads to upregulation of co-stimulatory molecules for better priming of T cells and secretion of inflammatory cytokines by innate immune cells1,2,3,4. Lymphocyte-deficient hosts often die of acute infection, presumably owing to their lack of an adaptive immune response to effectively clear pathogens. However, we show here that an unleashed innate immune response due to the absence of residential T cells can also be a direct cause of death. Viral infection or administration of poly(I:C), a ligand for TLR3, led to cytokine storm in T-cell- or lymphocyte-deficient mice in a fashion dependent on NK cells and tumor necrosis factor. We have further shown, through the depletion of CD4+ and CD8+ cells in wild-type mice and the transfer of T lymphocytes into Rag-1–deficient mice, respectively, that T cells are both necessary and sufficient to temper the early innate response. In addition to the effects of natural regulatory T cells, close contact of resting CD4+CD25Foxp3 or CD8+ T cells with innate cells could also suppress the cytokine surge by various innate cells in an antigen-independent fashion. Therefore, adaptive immune cells have an unexpected role in tempering initial innate responses.

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  1. 1.

    & Innate immunity: the virtues of a nonclonal system of recognition. Cell 91, 295–298 (1997).

  2. 2.

    et al. Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene. Science 282, 2085–2088 (1998).

  3. 3.

    & Protozoan encounters with Toll-like receptor signalling pathways: implications for host parasitism. Nat. Rev. Immunol. 6, 895–906 (2006).

  4. 4.

    & Cooperation of Toll-like receptor signals in innate immune defence. Nat. Rev. Immunol. 7, 179–190 (2007).

  5. 5.

    , , & Persistence of mouse hepatitis virus A59 RNA in a slow virus demyelinating infection in mice as detected by in situ hybridization. J. Virol. 51, 563–566 (1984).

  6. 6.

    & Mouse hepatitis virus. Curr. Opin. Microbiol. 4, 462–466 (2001).

  7. 7.

    & TLR3 in antiviral immunity: key player or bystander? Trends Immunol. 26, 462–468 (2005).

  8. 8.

    & Bacterial superantigens. Clin. Exp. Immunol. 133, 299–306 (2003).

  9. 9.

    et al. Mice deficient for the 55 kd tumor necrosis factor receptor are resistant to endotoxic shock, yet succumb to L. monocytogenes infection. Cell 73, 457–467 (1993).

  10. 10.

    , , & Septic shock: pathogenesis. Lancet 338, 732–736 (1991).

  11. 11.

    et al. CD4+CD25+ T(R) cells suppress innate immune pathology through cytokine-dependent mechanisms. J. Exp. Med. 197, 111–119 (2003).

  12. 12.

    , & Regulatory T cells prevent catastrophic autoimmunity throughout the lifespan of mice. Nat. Immunol. 8, 191–197 (2007).

  13. 13.

    et al. Regulatory T cell lineage specification by the forkhead transcription factor foxp3. Immunity 22, 329–341 (2005).

  14. 14.

    et al. Interaction between conventional dendritic cells and natural killer cells is integral to the activation of effective antiviral immunity. Nat. Immunol. 6, 1011–1019 (2005).

  15. 15.

    , , , & Functional interactions between dendritic cells and NK cells during viral infection. Nat. Immunol. 4, 175–181 (2003).

  16. 16.

    et al. Dendritic cells directly trigger NK cell functions: cross-talk relevant in innate anti-tumor immune responses in vivo. Nat. Med. 5, 405–411 (1999).

  17. 17.

    , & Dendritic cell maturation by innate lymphocytes: coordinated stimulation of innate and adaptive immunity. J. Exp. Med. 202, 203–207 (2005).

  18. 18.

    et al. NK-dependent DC maturation is mediated by TNFα and IFNγ released upon engagement of the NKp30 triggering receptor. Blood 106, 566–571 (2005).

  19. 19.

    , & Early T cell response to allografts occurring prior to alloantigen priming up-regulates innate-mediated inflammation and graft necrosis. Am. J. Pathol. 165, 147–157 (2004).

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We would like to acknowledge L. Su, H. Deng, X. Shi and Y. Liu for productive discussion and suggestions. We thank C.-R. Wang (University of Chicago) for MHC class II–deficient mice (originally from Jackson Laboratory), A.Y. Rudensky (Univ. Washington) for FoxP3 (GFP) knock-in mice and R. Baric (Univ. North Carolina) for the MHV-A59 virus and cell line. This research was in part supported by US National Institutes of Health grants AI062026, CA115540 and DK58891 to Y.X.F. and by a National Science Foundation of China grant (30430640) and Ministry of Science and Technology grants (2002CB513000, 2004BA519A61, 2006CB504300) to H.T. S.A. is part of the Medical Scientist Training Program at the University of Chicago and is supported by a Medical Scientist National Research Service Award (5 T32 GM07281).

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    • Kwang Dong Kim
    •  & Jie Zhao

    These authors contributed equally to this work.


  1. Center for Infection and Immunity and National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, 15 Da Tun Road, Chaoyang District, Beijing 100101, China.

    • Kwang Dong Kim
    • , Jie Zhao
    • , Xuanming Yang
    • , Peishuang Du
    • , Hong Tang
    •  & Yang-Xin Fu
  2. Department of Pathology, University of Chicago, Chicago, Illinois 60637, USA,

    • Kwang Dong Kim
    • , Sogyong Auh
    •  & Yang-Xin Fu


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K.D.K. and J.Z. conducted most of the experiments. S.A., X.Y. and P.D. provided technical support. S.A. and H.T. edited the paper. H.T. and Y.-X.F. organized and supervised the project. K.D.K. and Y.-X.F. wrote the manuscript.

Corresponding authors

Correspondence to Hong Tang or Yang-Xin Fu.

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