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CD28 induces immunostimulatory signals in dendritic cells via CD80 and CD86

Nature Immunology volume 5, pages 1134–1142 (2004)Cite this article

Abstract

Bidirectional signaling along the B7–CTLA-4 coreceptor pathway enables reciprocal conditioning of T cells and dendritic cells. Although T cells can instruct dendritic cells to manifest tolerogenic properties after CTLA-4 engagement of B7, such a B7-mediated signaling is not known to occur in response to CD28. Here we show that mouse dendritic cells were induced by soluble CD28 to express interleukin 6 and interferon-γ. Production of interleukin 6 required B7-1 (CD80), B7-2 (CD86) and p38 mitogen-activated protein kinase and prevented interferon-γ-driven expression of immunosuppressive tryptophan catabolism. In vivo, an adjuvant activity of soluble CD28 was demonstrated as enhanced T cell-mediated immunity to tumor and self peptides and protection against microbial and tumor challenge. Thus, different ligands of B7 can signal dendritic cells to express functionally distinct effector responses.

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Figure 1: Flow cytometry assessing the binding of CD28-Ig to cell transfectants and splenic DCs.
Figure 2: Cytokine production by DCs in vitro in response to CD28-Ig, CTLA-4–Ig or membrane-anchored CD28.
Figure 3: Cytokine induction by CD28-Ig requires B7 expression and p38 signaling.
Figure 4: CD28-Ig, CTLA-4–Ig and CD28 transfectants activate NF-κB- and MAPK-dependent transcription in B7-expressing DCs.
Figure 5: IL-6 has a dominant function in the effects of CD28-Ig in vitro.
Figure 6: CD28-Ig triggers IL-6-dependent adjuvant properties in B7-expressing DCs.
Figure 7: CD28-Ig and CTLA-4–Ig have disparate effects on DC ability to initiate immunity to C. albicans in vivo.
Figure 8: CD28-Ig interferes with CD4+CD25+ TR cell suppression in tumor-bearing mice.

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Acknowledgements

We thank V. Poli (University of Turin, Turin, Italy) for the gift of IL-6-deficient mice and G. Andrielli for technical assistance. Supported by the Italian Association for Cancer Research.

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Authors and Affiliations

  1. Department of Experimental Medicine, University of Perugia, Perugia, 06126, Italy

    Ciriana Orabona, Ursula Grohmann, Maria Laura Belladonna, Francesca Fallarino, Carmine Vacca, Roberta Bianchi, Silvia Bozza, Claudia Volpi, Maria Cristina Fioretti, Luigina Romani & Paolo Puccetti

  2. Centre National de la Recherche Scientifique UMR 7087, Hôpital Pitié-Salpêtrière, Paris, 75013, France

    Benoît L Salomon

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Supplementary information

Supplementary Fig. 1

CD28-Ig given in vivo initiates tumor-specific immunity. (PDF 29 kb)

Supplementary Fig. 2

Characterization of CD28-Ig fusion protein. (PDF 43 kb)

Supplementary Fig. 3

Cytofluorometric analysis of Jurkat cells stained with anti-CD28. (PDF 17 kb)

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Orabona, C., Grohmann, U., Belladonna, M. et al. CD28 induces immunostimulatory signals in dendritic cells via CD80 and CD86. Nat Immunol 5, 1134–1142 (2004). https://doi.org/10.1038/ni1124

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