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CD83 orchestrates immunity toward self and non-self in dendritic cells
Andreas B. Wild, … , Elisabeth Zinser, Alexander Steinkasserer
Andreas B. Wild, … , Elisabeth Zinser, Alexander Steinkasserer
Published September 17, 2019
Citation Information: JCI Insight. 2019;4(20):e126246. https://doi.org/10.1172/jci.insight.126246.
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Research Article Inflammation

CD83 orchestrates immunity toward self and non-self in dendritic cells

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Abstract

Dendritic cells (DCs) are crucial to balance protective immunity and autoimmune inflammatory processes. Expression of CD83 is a well-established marker for mature DCs, although its physiological role is still not completely understood. Using a DC-specific CD83–conditional KO (CD83ΔDC) mouse, we provide new insights into the function of CD83 within this cell type. Interestingly, CD83-deficient DCs produced drastically increased IL-2 levels and displayed higher expression of the costimulatory molecules CD25 and OX40L, which causes superior induction of antigen-specific T cell responses and compromises Treg suppressive functions. This also directly translates into accelerated immune responses in vivo. Upon Salmonella typhimurium and Listeria monocytogenes infection, CD83ΔDC mice cleared both pathogens more efficiently, and CD83-deficient DCs expressed increased IL-12 levels after bacterial encounter. Using the experimental autoimmune encephalomyelitis model, autoimmune inflammation was dramatically aggravated in CD83ΔDC mice while resolution of inflammation was strongly reduced. This phenotype was associated with increased cell influx into the CNS accompanied by elevated Th17 cell numbers. Concomitantly, CD83ΔDC mice had reduced Treg numbers in peripheral lymphoid organs. In summary, we show that CD83 ablation on DCs results in enhanced immune responses by dysregulating tolerance mechanisms and thereby impairing resolution of inflammation, which also demonstrates high clinical relevance.

Authors

Andreas B. Wild, Lena Krzyzak, Katrin Peckert, Lena Stich, Christine Kuhnt, Alina Butterhof, Christine Seitz, Jochen Mattner, Niklas Grüner, Maximilian Gänsbauer, Martin Purtak, Didier Soulat, Thomas H. Winkler, Lars Nitschke, Elisabeth Zinser, Alexander Steinkasserer

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Figure 4

Lack of CD83 on DCs enhances immune responses against intracellular bacteria.

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Lack of CD83 on DCs enhances immune responses against intracellular bact...
(A) BMDCs from CD83ΔDC or control mice were incubated with heat-killed Salmonella tympimurium (HKST) at a ratio of 10 bacteria per DC for 6 hours, and mRNA expression of Il12a, Il12b, and Il23a was assessed. Data are pooled from 3 independent experiments (n = 10). (B) Evaluation of IL-12p40 in the supernatants of BMDCs. Cells were stimulated with HKST at a ratio of 10 bacteria per DC for 16 hours, and supernatants were assessed by ELISA (n = 9, from 3 experiments). (C) Infection of CD83ΔDC and control mice with S. typhimurium (n = 9; 1 representative experiment is shown). Mice were treated with 1.0 × 107 CFU intragastric (i.g.) and sacrificed 4 days later. (D) Infection of CD83ΔDC and control mice with L. monocytogenes. Mice were infected intravenously with 1.0 × 104 CFU and were sacrificed 3 days later. Bacterial burden in liver and spleen was assessed by CFU counting of organ homogenates after 48 hours (n = 15, pooled from 3 independent experiments). Data are represented as mean ± SEM. Statistical analysis was performed using Mann-Whitney U test. *P < 0.05; ***P < 0.001; ns, not significant.

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