Abstract
Cross-priming allows dendritic cells (DCs) to induce cytotoxic T cell (CTL) responses to extracellular antigens. DCs require cognate 'licensing' for cross-priming, classically by helper T cells. Here we demonstrate an alternative mechanism for cognate licensing by natural killer T (NKT) cells recognizing microbial or synthetic glycolipid antigens. Such licensing caused cross-priming CD8α+ DCs to produce the chemokine CCL17, which attracted naive CTLs expressing the chemokine receptor CCR4. In contrast, DCs licensed by helper T cells recruited CTLs using CCR5 ligands. Thus, depending on the type of antigen they encounter, DCs can be licensed for cross-priming by NKT cells or helper T cells and use at least two independent chemokine pathways to attract naive CTLs. Because these chemokines acted synergistically, this can potentially be exploited to improve vaccinations.
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Acknowledgements
We thank W. Keßler (University of Greifswald) for CCR4-deficient mice; F. Tacke (University of Aachen) for CD1d- and MHC class II–deficient mice; R. Goldszmid (National Institute of Allergy and Infectious Diseases, National Institutes of Health) for CD8-deficient mice; J. Alferink (University of Bonn) for CCL17-eGFP knock-in mice; A. Peters for technical assistance; C. Coch and Rolf Fimmers for advice on statistics; and the Central Animal Facilities and the Flow Cytometry Core Facility at the Institutes of Molecular Medicine and Experimental Immunology for support. Supported by the Deutsche Forschungsgemeinschaft (Sonderforschungsbereich 704 grants A1 (I.F.), A2 (C.K.), A5 (P.A.K.) and A8 (W.K.), and Klinische Forschergruppe 228 grants P1 (U.P.) and P5 (C.K.)), the Australian National Health and Medical Research Council (D.I.G. and J.R.) and the Australian Research Council (J.R.).
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V.S. and V.L-K. designed and did most experiments, analyzed and interpreted data and contributed to the writing of the manuscript; C.A.T., T.Q. and K.H. designed, did and analyzed individual experiments; U.P., J.R., P.P., J.C., D.I.G., P.B.S., P.A.K., W.K. and I.F. contributed tools, discussed and interpreted results and edited the manuscript; and C.K. conceived the project, designed and interpreted experiments and wrote the manuscript.
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Supplementary Text and Figures
Supplementary Figures 1–16 (PDF 3572 kb)
Supplementary Movie 1
Short DC contact duration when CTL had not been exposed to α-GC. (MOV 962 kb)
Supplementary Movie 2
Long DC contact duration when CTL had been exposed to α-GC. (MOV 833 kb)
Supplementary Movie 3
Impaired migration of CCR4-competent CTL towards DCs that cannot produce CCL17 (MOV 1035 kb)
Supplementary Movie 4
Impaired migration of CCR4-deficient CTL towards CCL17-producing DCs. (MOV 1161 kb)
Supplementary Movie 5
Direct comparison of migration of CCR4-competent and –deficient CTL towards CCL17-producing DCs. (MOV 1219 kb)
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Semmling, V., Lukacs-Kornek, V., Thaiss, C. et al. Alternative cross-priming through CCL17-CCR4-mediated attraction of CTLs toward NKT cell–licensed DCs. Nat Immunol 11, 313–320 (2010). https://doi.org/10.1038/ni.1848
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DOI: https://doi.org/10.1038/ni.1848
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