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Induction of innate and adaptive immunity by delivery of poly dA:dT to dendritic cells

Nature Chemical Biology volume 9, pages 250–256 (2013)Cite this article

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Abstract

Targeted delivery of antigens to dendritic cells (DCs) is a promising vaccination strategy. However, to ensure immunity, the approach depends on coadministration of an adjuvant. Here we ask whether targeting of both adjuvant and antigen to DCs is sufficient to induce immunity. Using a protein ligation method, we develop a general approach for linking the immune stimulant, poly dA:dT (pdA:dT), to a monoclonal antibody (mAb) specific for DEC205 (DEC). We show that DEC-specific mAbs deliver pdA:dT to DCs for the efficient production of type I interferon in human monocyte-derived DCs and in mice. Notably, adaptive T-cell immunity is elicited when mAbs specific for DEC–pdA:dT are used as the activation stimuli and are administered together with a DC-targeted antigen. Collectively, our studies indicate that DCs can integrate innate and adaptive immunity in vivo and suggest that dual delivery of antigen and adjuvant to DCs might be an efficient approach to vaccine development.

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Figure 1: Design and synthesis of anti–DEC-pdA:dT.
Figure 2: Anti–hDEC-pdA:dT activates human MoDCs.
Figure 3: RIG-I is necessary for DCs activation by anti–hDEC-pdA:dT.
Figure 4: Anti–mDEC-pdA:dT triggers type I IFN production in vivo.
Figure 5: DCs drive bulk production of type I IFN triggered by anti–mDEC-pdA:dT.
Figure 6: Delivery of adjuvant and antigen to DCs induces adaptive immune responses.

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Acknowledgements

The authors thank members of the Steinman and Muir laboratories for many valuable discussions. Funding was provided by National Institutes of Health Grants GM086868 (to T.W.M.), AI013013 (to R.M.S.), a Foundation for the National Institutes of Health Gates Foundation grant no. 334 (to R.M.S.) and a graduate fellowship to S. Barbuto by NIH MSTP grant GM07739.

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Author notes

  1. Miquel Vila-Perelló & Tom W Muir

    Present address: Present address: Department of Chemistry, Frick Chemistry Laboratory, Princeton University, Princeton, New Jersey, USA.,

  2. Scott Barbuto, Juliana Idoyaga and Ralph M Steinman: S.B. and J.I. contributed equally to this work.

Authors and Affiliations

  1. Laboratory of Synthetic Protein Chemistry, The Rockefeller University, New York, New York, USA

    Scott Barbuto, Miquel Vila-Perelló & Tom W Muir

  2. Laboratory of Cellular Physiology and Immunology, The Rockefeller University, New York, New York, USA

    Scott Barbuto, Juliana Idoyaga, Maria P Longhi, Gaëlle Breton & Ralph M Steinman

  3. Chris Browne Center for Immunology and Immune Diseases, The Rockefeller University, New York, New York, USA

    Scott Barbuto, Juliana Idoyaga, Maria P Longhi & Gaëlle Breton

  4. R.M.S. regrettably passed away on September 30, 2011.,

    Ralph M Steinman

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Contributions

R.M.S. and T.W.M. conceived the original idea and contributed equally to this manuscript. T.W.M., S.B. and M.V.-P. contributed to the design and discussion of the chemical work; R.M.S., S.B. and J.I. contributed to the design and discussion of the biological work; S.B. and M.V.-P. synthesized and characterized mAb–pdA:dT conjugates; S.B. performed experiments with MoDCs with help from G.B.; S.B. and J.I. performed experiments in vivo with help and advice from M.P.L.; S.B., J.I. and M.V.-P. analyzed data and prepared figures; S.B., J.I., M.V.-P. and T.W.M. wrote the manuscript. All authors edited the manuscript.

Corresponding author

Correspondence to Tom W Muir.

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Barbuto, S., Idoyaga, J., Vila-Perelló, M. et al. Induction of innate and adaptive immunity by delivery of poly dA:dT to dendritic cells. Nat Chem Biol 9, 250–256 (2013). https://doi.org/10.1038/nchembio.1186

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