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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 3

Ablation of CD83 boosts DC-mediated proinflammatory T cell responses.

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Ablation of CD83 boosts DC-mediated proinflammatory T cell responses.
(A...
(A and B) Analysis of stimulatory capacity toward T cells. (A) BMDCs from CD83ΔDC or control mice were activated with 3.5 μg/mL CpG ODN2395 and 1 μg/mL Pam3CSK4 (TLR-Ls) and pulsed with 2 μg/mL MOG35–55 for 3 hours and cocultivated with CellTrace Violet–labeled (CTV-labeled) 2D2-transgenic CD4+ T cells. Proliferation was analyzed after 3 days of coculture via dye dilution on a flow cytometer. (B) Quantification of proliferative potential of T cells calculated from the ratio of median fluorescence of CTV. Data are pooled from 5 experiments (n = 14). (C) Proliferative response of 2D2 T cells to BMDCs in the presence of 10 μg/mL anti‑OX40L (α-OX40L) or isotype-matched control antibody (n = 7, pooled from 2 independent experiments). (D) Assessment of cytokine secretion in BMDC–T cell cocultures. BMDCs were treated with TLR-Ls for 16 hours, and cytokine content in the supernatants were analyzed via cytometric bead array (n = 8 from 3 experiments). (E) Suppressive capacity of Tregs in cocultures. Tregs and effector T (Teff) cells were cultured at different ratios with TLR-L–activated, MOG-pulsed BMDCs for 4 days (n = 6). Data are represented as mean ± SEM. Statistical analysis was performed using Mann-Whitney U test or 1-way ANOVA with Holm-Šídák correction for multiple comparisons (only for C). *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001; ns, not significant.

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