Research ArticleNEUROIMMUNOLOGY

Conventional DCs sample and present myelin antigens in the healthy CNS and allow parenchymal T cell entry to initiate neuroinflammation

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Science Immunology  25 Jan 2019:
Vol. 4, Issue 31, eaau8380
DOI: 10.1126/sciimmunol.aau8380

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Licensing myelin-reactive T cells

Multiple distinct populations of potential antigen-presenting cells (APCs) are interspersed among the different anatomical components of the brain, including microglia, B lymphocytes, macrophages, and dendritic cells (DCs). Mundt et al. investigated which steady-state APC types are responsible for displaying peptide fragments of myelin proteins to pathogenic CD4+ T cells with the capacity to initiate neuroinflammatory disorders such as human multiple sclerosis. Adoptive transfer of myelin-reactive CD4+ T cells to mice with conditional deletion of MHC class II molecules in specific brain APC subsets identified conventional DCs as the essential APCs enabling initiation of T cell–mediated immunopathology. The results of this study will assist in the precision targeting of immunotherapies aimed at restraining rogue T cells responsible for human neuroinflammatory diseases.

Abstract

The central nervous system (CNS) is under close surveillance by immune cells, which mediate tissue homeostasis, protection, and repair. Conversely, in neuroinflammation, dysregulated leukocyte invasion into the CNS leads to immunopathology and neurological disability. To invade the brain parenchyma, autoimmune encephalitogenic T helper (TH) cells must encounter their cognate antigens (Ags) presented via local Ag-presenting cells (APCs). The precise identity of the APC that samples, processes, and presents CNS-derived Ags to autoaggressive T cells is unknown. Here, we used a combination of high-dimensional single-cell mapping and conditional MHC class II ablation across all CNS APCs to systematically interrogate each population for its ability to reactivate encephalitogenic TH cells in vivo. We found a population of conventional dendritic cells, but not border-associated macrophages or microglia, to be essential for licensing T cells to initiate neuroinflammation.

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