CD28 induces immunostimulatory signals in dendritic cells via CD80 and CD86

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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Correspondence to Paolo Puccetti.

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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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