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 September 18, 2018
Citation Information: J Clin Invest. 2018;128(12):5322-5334. https://doi.org/10.1172/JCI123708.
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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 1

CD26+ZBTB46+ cDCs accumulate in the CNS during adoptively transferred EAE.

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CD26+ZBTB46+ cDCs accumulate in the CNS during adoptively transferred EA...
EAE was induced by adoptive transfer of WT myelin-primed CD4+ Th17 cells into naive syngeneic hosts. (A) Brain mononuclear cells were harvested at peak EAE and analyzed by flow cytometry. Dot plots are gated on the population indicated directly above each plot. The numbers indicate percentage of the gated population. The data are representative of 3 experiments. (B) MHCII+CD11c+ CD88+ or CD26+ cells were purified from the CNS (n = 3 per group) by flow sorting, and gene expression was measured by Nanostring nCounter analysis. Genes with a false discovery rate (FDR) less than 0.10 are identified in the heatmaps. The right panel shows Flt3, Tlr3, and Tlr4 mRNA levels in paired DC subsets from individual mice. P values were determined by paired, 2-tailed Student’s t test. **P < 0.01. (C and D) Expression of ZBTB46 was measured in MHCII+CD11c+ CD26+ or CD88+ brain mononuclear cells, harvested at peak EAE, by flow cytometry. The open histograms reflect intracellular staining with anti-ZBTB46 antibodies (C) or GFP expression in cells from Zbtb46gfp/+ reporter mice (D). The shaded gray histograms reflect the isotype (C) or nonreporter control (D).