Editors' ChoiceMultiple Sclerosis

Myeloid cells: The Trojan horse for T cell invasion into the brain

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Science Translational Medicine  27 Nov 2019:
Vol. 11, Issue 520, eaaz9757
DOI: 10.1126/scitranslmed.aaz9757


C-type lectin receptors on myeloid cells regulate the activation and infiltration of T cells into the central nervous system in experimental autoimmune encephalomyelitis.

Multiple sclerosis (MS) is a chronic demyelinating disease of the central nervous system (CNS) leading to neuronal dysfunction and disability. The infiltration of autoreactive CD4+ T cells into CNS is thought to play an important role in MS pathogenesis. Nevertheless, the mechanisms governing CD4+ T cells activation and infiltration remain mostly unknown. In this study, N'diaye et al. analyzed CD4+ T cells activation/infiltration in myelin oligodendrocyte glycoprotein (MOG)–induced experimental autoimmune encephalomyelitis (EAE), an animal model of MS.

Taking advantage of the Dark Agouti (DA) rat strain, which is highly susceptible to EAE and the Piebald Virol Glaxo (PVG) strain that is resistant, the authors generated a congenic strain (CLRc) enabling the transferring of a cluster of resistant genes that protected against EAE. Following the characterization of the protective effects in CLRc rates by a combination of histopathological analyses of demyelination, weight loss, and disease incidence, they identified five potential resistant genes of the CLR Dectin-2 family. Of the genes identified, the Mcl and Mincle correlated with the protection and qPCR analyses revealed a decrease in their expression in CLRc relative to the DA strain. Moreover, myeloid cells reflected the decrease expression of Mcl/Mincle, suggesting the protective effects are associated with impaired myeloid cells signaling. Stimulation of CLRc bone-derived macrophages/dendritic cells (BMDMD) with Mcl/Mincle-specific ligands showed a reduced cytokines production compared with stimulated DA-BMDMD further implicating an impairment in myeloid cell signaling. To investigate if the impaired Mcl/Mincle signaling in myeloid cells altered T cell reactivation, the authors cocultured MOG-specific resting effector T cells with CLRc BMDMD cells, which led to a decrease in T cell proliferation, cytokine production, and reduced migration. The analysis of CD4+ T cells in the spinal cord of diseased DA and CLRc rats further revealed a significant decrease in CD4+ T cells in CLRc rats, supporting an impairment in infiltration. The authors next showed that siRNA-mediated gene silencing of Mcl/Mincle or suppressing their ligand SAP130 protected against EAE. Lastly, histopathological analysis of patients with MS demonstrated that MCL and MINCLE are expressed in MS lesions.

By generating congenic rats expressing lower levels of Mcl and Mincle on myeloid cells, this study revealed their expression is critical for T cell recruitment and activation in a model of MS. Moreover, gene silencing of Mcl/Mincle or blockage of their endogenous ligand protected against EAE supporting a potential therapeutic target for MS. Future studies should evaluate whether in myeloid cell Mcl/Mincle signaling also plays a role in the recruitment of T cell or potentially other immune cells following head trauma or brain ischemia.

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