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Toll-like receptors control activation of adaptive immune responses

Nature Immunology volume 2, pages 947–950 (2001)Cite this article

Abstract

Mechanisms that control the activation of antigen-specific immune responses in vivo are poorly understood. It has been suggested that the initiation of adaptive immune responses is controlled by innate immune recognition. Mammalian Toll-like receptors play an essential role in innate immunity by recognizing conserved pathogen-associated molecular patterns and initiating the activation of NF-κB and other signaling pathways through the adapter protein, MyD88. Here we show that MyD88-deficient mice have a profound defect in the activation of antigen-specific T helper type 1 (TH1) but not TH2 immune responses. These results suggest that distinct pathways of the innate immune system control activation of the two effector arms of adaptive immunity.

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Figure 1: MyD88-deficient lymphocytes had no intrinsic defects in development and function.
Figure 2: Antigen-specific TH1 cell responses were impaired in MyD88-deficient mice.
Figure 3: Antigen-specific TH2-dependent immunoglobulin production was independent of MyD88.
Figure 4: Increased antigen-specific IL-13 production in MyD88-deficient lymph node cells.
Figure 5: Maturation of dendritic cells by mycobacteria requires MyD88.

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References

  1. Janeway, C. A. Jr Approaching the asymptote? Evolution and revolution in immunology. Cold Spring Harb. Symp. Quant. Biol. 54, 1–13 (1989).

    Article  CAS  Google Scholar 

  2. Lemaitre, B., Nicolas, E., Michaut, L., Reichhart, J. M. & Hoffmann, J. A. The dorsoventral regulatory gene cassette spatzle/Toll/cactus controls the potent antifungal response in Drosophila adults. Cell 86, 973–983 (1996).

    Article  CAS  Google Scholar 

  3. Medzhitov, R., Preston-Hurlburt, P. & Janeway, C. A. Jr A human homologue of the Drosophila Toll protein signals activation of adaptive immunity. Nature 388, 394–397 (1997).

    Article  CAS  Google Scholar 

  4. Medzhitov, R. & Janeway, C. A. Jr Innate immunity: the virtues of a nonclonal system of recognition. Cell 91, 295–298 (1997).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  6. Takeuchi, O. et al. Differential roles of TLR2 and TLR4 in recognition of gram-negative and gram-positive bacterial cel wall components. Immunity 11, 443–451 (1999).

    Article  CAS  Google Scholar 

  7. Fearon, D. T. & Locksley, R. M. The instructive role of innate immunity in the acquired immune response. Science 272, 50–53 (1996).

    Article  CAS  Google Scholar 

  8. Medzhitov, R. et al. MyD88 is an adaptor protein in the hToll/IL-1 receptor family signaling pathways. Mol. Cell 2, 253–258 (1998).

    Article  CAS  Google Scholar 

  9. Muzio, M., Natoli, G., Saccani, S., Levrero, M. & Mantovani, A. The human toll signaling pathway: divergence of nuclear factor κB and JNK/SAPK activation upstream of tumor necrosis factor receptor- associated factor 6 (TRAF6). J. Exp. Med. 187, 2097–2101 (1998).

    Article  CAS  Google Scholar 

  10. Kawai, T., Adachi, O., Ogawa, T., Takeda, K. & Akira, S. Unresponsiveness of MyD88-deficient mice to endotoxin. Immunity 11, 115–122 (1999).

    Article  CAS  Google Scholar 

  11. Kaisho, T., Takeuchi, O., Kawai, T., Hoshino, K. & Akira, S. Endotoxin-induced maturation of MyD88-deficient dendritic cells. J. Immunol. 166, 5688–5694. (2001).

    Article  CAS  Google Scholar 

  12. Wesche, H., Henzel, W. J., Shillinglaw, W., Li, S. & Cao, Z. MyD88: an adapter that recruits IRAK to the IL-1 receptor complex. Immunity 7, 837–847 (1997).

    Article  CAS  Google Scholar 

  13. Muzio, M., Ni, J., Feng, P. & Dixit, V. M. IRAK (Pelle) family member IRAK-2 and MyD88 as proximal mediators of IL- 1 signaling. Science 278, 1612–1615 (1997).

    Article  CAS  Google Scholar 

  14. Adachi, O. et al. Targeted disruption of the MyD88 gene results in loss of IL-1– and IL-18–mediated function. Immunity 9, 143–150 (1998).

    Article  CAS  Google Scholar 

  15. Fantuzzi, G. & Dinarello, C. A. Interleukin-18 and interleukin-1β: two cytokine substrates for ICE (caspase-1). J. Clin. Immunol. 19, 1–11 (1999).

    Article  CAS  Google Scholar 

  16. Banchereau, J. & Steinman, R. M. Dendritic cells and the control of immunity. Nature 392, 245–252 (1998).

    Article  CAS  Google Scholar 

  17. Satoskar, A. R. et al. Enhanced Th2-like responses in IL-1 type 1 receptor-deficient mice. Eur. J. Immunol. 28, 2066–2074 (1998).

    Article  CAS  Google Scholar 

  18. Takeda, K. et al. Defective NK cell activity and Th1 response in IL-18-deficient mice. Immunity 8, 383–390 (1998).

    Article  CAS  Google Scholar 

  19. Townsend, M. J., Fallon, P. G., Matthews, D. J., Jolin, H. E. & McKenzie, A. N. T1/ST2-deficient mice demonstrate the importance of T1/ST2 in developing primary T helper cell type 2 responses. J. Exp. Med. 191, 1069–1076 (2000).

    Article  CAS  Google Scholar 

  20. Hoshino, K. et al. The absence of interleukin 1 receptor-related T1/ST2 does not affect T helper cell type 2 development and its effector function. J. Exp. Med. 190, 1541–1548 (1999).

    Article  CAS  Google Scholar 

  21. Underhill, D. M., Ozinsky, A., Smith, K. D. & Aderem, A. Toll-like receptor-2 mediates mycobacteria-induced proinflammatory signaling in macrophages. Proc. Natl Acad. Sci. USA 96, 14459–14463 (1999).

    Article  CAS  Google Scholar 

  22. Means, T. K. et al. Human toll-like receptors mediate cellular activation by Mycobacterium tuberculosis. J. Immunol. 163, 3920–3927 (1999).

    CAS  PubMed  Google Scholar 

  23. Erb, K. J. Atopic disorders: a default pathway in the absence of infection? Immunol. Today 20, 317–322 (1999).

    Article  CAS  Google Scholar 

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Acknowledgements

We thank C. A. Janeway and R. A. Flavell for the 1H3.1 TCR–transgenic and caspase-1–deficient mice, respectively. R. M. thanks C. A. Janeway for critical reading of the manuscript and continuous support. Supported by Howard Hughes Medical Institute, NIH (AI44220-01) and Searle (to R. M.) and by Deutsche Forschungsgemeinschaft (to M. S.).

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Author notes

  1. Markus Schnare and Gregory M. Barton: These authors contributed equally to this work.

Authors and Affiliations

  1. Section of Immunobiology, Yale University School of Medicine, New Haven, 06520, CT, USA

    Markus Schnare, Gregory M. Barton, Agnieszka Czopik Holt & Ruslan Medzhitov

  2. Howard Hughes Medical Institute, New Haven, 06520, CT, USA

    Markus Schnare, Gregory M. Barton & Ruslan Medzhitov

  3. Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, Suita, 565-0871, Osaka, Japan

    Kiyoshi Takeda & Shizuo Akira

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  1. Markus Schnare
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Correspondence to Ruslan Medzhitov.

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Schnare, M., Barton, G., Holt, A. et al. Toll-like receptors control activation of adaptive immune responses. Nat Immunol 2, 947–950 (2001). https://doi.org/10.1038/ni712

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