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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 2

CD83 deficiency on DCs leads to enhanced costimulatory capacity.

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CD83 deficiency on DCs leads to enhanced costimulatory capacity.
(A) Flo...
(A) Flow cytometry analysis of costimulatory surface markers. BMDCs were stimulated with 3.5 μg/mL CpG ODN2395 and 1 μg/mL Pam3CSK4 (TLR-Ls) for 16 hours, and expression of CD86, CD25, and OX40L was assessed on CD11c+MHC-IIhi mature DCs via flow cytometry. FACS data are pooled from 6 independent experiments, and the median fluorescence intensity was normalized to control animals (n = 20). (B) Western blot of cytoplasmic lysates of BMDCs unstimulated and probed against IRAK1. See full, uncut gels in online supplemental material. (C) Quantification of IRAK1 amounts in lysates from BMDCs (n = 5). (D) Expression of IL-2 after stimulation of DCs. BMDCs were stimulated with TLR-Ls for 6 hours, and expression of Il2 mRNA was analyzed via qPCR (n = 18–20, pooled from 7 experiments). (E) Assessment of IL-2 secretion by BMDCs in response to TLR-Ls via ELISA. BMDCs were stimulated with TLR-Ls, and supernatant was collected after 16 hours (n = 19, pooled from 8 experiments). (F) Assessment of Nfatc2 in nuclear lysates from BMDCs. BMDCs were stimulated with TLR-Ls for indicated periods, harvested, and sequentially lysed (cytoplasm and nucleus). Nuclear fraction was separated with SDS-PAGE and transferred onto nitrocellulose membranes and probed with Nfatc2. Loading control for nuclear fraction was Lamin A/C. Blot is representative of 4 experiments. See full, uncut gels in online supplemental material. Data are represented as mean ± SEM (A, C, D, E). Statistical analysis was performed using Mann-Whitney U test. *P < 0.05; ****P < 0.0001.

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