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⇱ Adaptive immune cells temper initial innate responses | Nature Medicine

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Abstract

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+CD25−Foxp3− 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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Figure 1: Comparison of mortality rates, liver virus titers and serum inflammatory cytokines of wild-type BALB/c mice and nude mice after MHV-A59 infection.
The alternative text for this image may have been generated using AI.
Figure 2: Wild-type mice are more resistant to poly(I:C) than nude mice and Rag-1 knockout mice, and T cells are essential for controlling proinflammatory cytokine production in vivo.
The alternative text for this image may have been generated using AI.
Figure 3: T cells inhibit proinflammatory cytokine production of splenocytes stimulated with poly(I:C) in vitro.
The alternative text for this image may have been generated using AI.
Figure 4: TNFR-hIg can substantially improve survival rates among nude and Rag-1 knockout mice treated with poly(I:C), and NK cells are critical in the sudden death of Rag-1 knockout mice after poly(I:C) injection.
The alternative text for this image may have been generated using AI.

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Acknowledgements

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).

Author information

Author notes

  1. Kwang Dong Kim and Jie Zhao: These authors contributed equally to this work.

Authors and Affiliations

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

    Kwang Dong Kim, Jie Zhao, Xuanming Yang, Peishuang Du, Hong Tang & Yang-Xin Fu

  2. Department of Pathology, University of Chicago, Chicago, 60637, Illinois, USA

    Kwang Dong Kim, Sogyong Auh & Yang-Xin Fu

Contributions

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.

Supplementary information

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Dong Kim, K., Zhao, J., Auh, S. et al. Adaptive immune cells temper initial innate responses. Nat Med 13, 1248–1252 (2007). https://doi.org/10.1038/nm1633

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