CNS-resident classical DCs play a critical role in CNS autoimmune disease
David A. Giles, … , Jesse M. Washnock-Schmid, Benjamin M. Segal
David A. Giles, … , Jesse M. Washnock-Schmid, Benjamin M. Segal
Published December 3, 2018; First published September 18, 2018
Citation Information: J Clin Invest. 2018;128(12):5322-5334. https://doi.org/10.1172/JCI123708.
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Categories: Research Article Autoimmunity Neuroscience

CNS-resident classical DCs play a critical role in CNS autoimmune disease

Abstract

Experimental autoimmune encephalomyelitis (EAE) is an inflammatory demyelinating disease of the central nervous system (CNS), induced by the adoptive transfer of myelin-reactive CD4+ T cells into naive syngeneic mice. It is widely used as a rodent model of multiple sclerosis (MS). The development of EAE lesions is initiated when transferred CD4+ T cells access the CNS and are reactivated by local antigen-presenting cells (APCs) bearing endogenous myelin peptide/MHC class II complexes. The identity of the CNS-resident, lesion-initiating APCs is widely debated. Here we demonstrate that classical dendritic cells (cDCs) normally reside in the meninges, brain, and spinal cord in the steady state. These cells are unique among candidate CNS APCs in their ability to stimulate naive, as well as effector, myelin-specific T cells to proliferate and produce proinflammatory cytokines directly ex vivo. cDCs expanded in the meninges and CNS parenchyma in association with disease progression. Selective depletion of cDCs led to a decrease in the number of myelin-primed donor T cells in the CNS and reduced the incidence of clinical EAE by half. Based on our findings, we propose that cDCs, and the factors that regulate them, be further investigated as potential therapeutic targets in MS.

Authors

David A. Giles, Patrick C. Duncker, Nicole M. Wilkinson, Jesse M. Washnock-Schmid, Benjamin M. Segal

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Figure 4

CNS moDCs express iNOS and Arg1 and efficiently phagocytose myelin.

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CNS moDCs express iNOS and Arg1 and efficiently phagocytose myelin. (A) ...
(A) EAE was induced by active immunization with myelin peptide, and CNS mononuclear cells were isolated at clinical onset (left panels) or peak disease (right panels). Expression of inducible nitric oxide synthase (iNOS) and arginase-1 (Arg1) in CD88+ or CD26+ CNS DCs was assessed by intracellular flow cytometry. All of the dot plots are gated on MHCII+CD11c+ cells. Cells in the CD88 versus CD26 dot plots are color coded based on patterns of iNOS and Arg1 expression. (B) EAE was induced by adoptive transfer of WT myelin-primed Th17 cells. Mononuclear cells were isolated from the CNS at the peak of EAE and cultured overnight with unlabeled or pHrodo-labeled purified myelin. Phagocytosis was measured as the percentage of pHrodo+ cells within gated CD26+ or CD88+ DC populations. Each symbol represents a data point generated from a single mouse. Connected symbols indicate paired samples from the same mouse. Data are representative of 2 experiments. *P < 0.05 by paired, 2-tailed Student’s t test. n = 3–5 mice per group or condition.